Bio

Honors & Awards


  • Wellcome Visiting Professor, Medical College of Virginia (11/92)
  • 1991 Young Investigator Award, Western Society for Clinical Investigation (02/91)
  • Speaker, Leukemia Society of America Speaker, UCLA (06/89)
  • Established Investigator Award, American Heart Association (07/87-06/92)
  • Scholar Award (funding declined because of AHA Award), Leukemia Society of America (07/87)
  • Faculty Research Award (funding declined because of AHA Award), American Cancer Society (07/87)
  • Postdoctoral Fellowship, John A. and George L. Hartford Fellowship (07/84-06/87)
  • Mellon Foundation Fellowship, Stanford University (09/83-08/84)
  • Hume Faculty Scholar, Stanford University (09/82-08/83)
  • National Research Service Award (Postdoctoral Fellowship), NIAID, NIH (02/80-01/82)
  • Postdoctoral Fellowship, The Jane Coffin Childs Memorial Fund for Medical Research (08/78-01/80)
  • A.B. summa cum laude, Radcliffe College (1972)
  • National Merit Scholar, National Merit Scholarship Corporation (1968)

Professional Education


  • M.D., Harvard Medical School, Medicine (1976)
  • A.B., Radcliffe College, Cambridge, MA, Biochemical Sciences (1972)

Research & Scholarship

Current Research and Scholarly Interests


CD72 is a B lymphocyte surface protein expressed from early stages of B cell development through to the mature B cell stage, but its expression is turned off as B cells differentiate into plasma cells. To elucidate the function of CD72 we have used gene targeting to generate homozygous mutant mice that totally lack CD72 expression. The B cells in these mice are hyper-responsive to stimulation through the B cell receptor. These data indicate that CD72 plays a negative regulatory role on B cell responsiveness. In accord with our findings, an ITIM motif in the cytoplasmic tail of CD72 has been shown to bind to the tyrosine phosphatase SHP-1, a feature characteristic of other surface proteins that negatively regulate lymphocyte responses. We postulate that CD72 is involved in setting the threshold for B cell responsiveness and that it therefore plays an important role in B cell repertoire selection. Our current studies are examining how CD72 regulates the balance between B cell tolerance and autoimmunity in several model systems. We have evidence that the CD72-deficient mice are more susceptible to the induced autoimmune disease experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. We are studying the mechanisms responsible for the increased severity of disease in CD72-deficient mice. CD72-deficient mice also develop spontaneous autoimmune disease as they age, characterized by production of antinuclear antibodies including anti-single-stranded- and anti-double-stranded-DNA antibodies and eventual development of glomerulonephritis. Current studies are aimed at further characterizing the autoantibodies produced, determining the regulatory changes responsible for their production, as well as their pathogenicity. We are additionally studying the mechanisms by which CD72-deficiency leads to a partial abrogation of B cell anergic tolerance in mice in which all B cells express a transgenic B cell receptor specific for hen-egg lysozyme (HEL) and in which the antigen HEL is expressed in the serum. Finally, the lab is examining the biochemistry of signaling through CD72 to determine the molecular mechanisms by which CD72 regulates B cell responsiveness.

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Medicine on a need-to-know basis NATURE IMMUNOLOGY Busch, R., Byrne, B., Gandrud, L., Sears, D., Meyer, E., Kattah, M., Kurihara, C., Haertel, E., Parnes, J. R., Mellins, E. D. 2006; 7 (6): 543-547

    Abstract

    Disease-oriented, introductory medical curricula can help overcome educational and institutional barriers that separate aspiring translational scientists in PhD programs from the world of medicine.

    View details for Web of Science ID 000237751200004

    View details for PubMedID 16715061

  • CD72 down-modulates BCR-induced signal transduction and diminishes survival in primary mature B lymphocytes JOURNAL OF IMMUNOLOGY Li, D. H., Tung, J. W., Tarner, I. H., Snow, A. L., Yukinari, T., Ngernmaneepothong, R., Martinez, O. M., Parnes, J. R. 2006; 176 (9): 5321-5328

    Abstract

    CD72, a 45-kDa type II transmembrane glycoprotein carrying an ITIM motif, is believed to be an inhibitory coreceptor of the BCR. Mature B cells lacking CD72 show enhanced Ca(2+) mobilization and are hyperproliferative in response to BCR ligation. However, the signal transduction pathways downstream of BCR signaling that transmit the inhibitory effect of CD72 in mature B cells remain unknown. To address this question, we used hen egg lysozyme-specific BCR transgenic mice to elucidate the differential cell signaling between wild-type and CD72-deficient B cells in response to hen egg lysozyme Ag stimulation. Our results demonstrate that CD72 predominantly down-regulates the major signal transduction pathways downstream of the BCR, including NF-AT, NF-kappaB, ERK, JNK, p38-MAPK, and PI3K/Akt in mature B cells. CD72 ligation with anti-CD72 Ab (K10.6), which mimics the binding of CD100 (a natural ligand for CD72) to release the inhibitory function of CD72, augments cell proliferation, Ca(2+) flux, IkappaBalpha activation, and ERK MAPK activity upon Ag stimulation in wild-type B cells. In addition, we show direct evidence that CD72 promotes cell cycle arrest and apoptosis after Ag stimulation in mature B cells. Taken together, our findings conclude that CD72 plays a dominant role as a negative regulator of BCR signaling in primary mature B lymphocytes.

    View details for Web of Science ID 000238768700028

    View details for PubMedID 16621999

  • Mouse splenic B lymphocyte activation using different activation stimuli induces in vitro splicing of tumor necrosis factor-alpha nuclear pre-mRNA MOLECULAR IMMUNOLOGY Li, Y. Y., Yang, Y., Bao, M., Edwards, C. K., Parnes, J. R. 2006; 43 (6): 613-622

    Abstract

    The pleiotropic functions of tumor necrosis factor-alpha (TNFalpha) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFalpha is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced "pre-mRNA" of TNFalpha is present in resting T cells. Initiation of splicing of TNFalpha pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFalpha production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mvarphi) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFalpha mRNA. The physiological process of B cell activation induced by (1) either the cross-linking of the B cell receptor (BCR) or CD40, (2) treatment with LPS, or PMA plus ionomycin, induces TNFalpha mRNA splicing in vitro. The kinetic response of TNFalpha splicing in B cells is much slower when compared to that in activated T cells. Studies using well-known kinase inhibitors demonstrated that MAP kinase kinase (MEK) and protein kinase C (PKC) are required for TNFalpha splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFalpha in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFalpha in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFalpha therapy.

    View details for DOI 10.1016/j.molimm.2005.04.010

    View details for Web of Science ID 000234952300014

    View details for PubMedID 15899518

  • Dual regulation of BCR-mediated growth inhibition signaling by CD72 EUROPEAN JOURNAL OF IMMUNOLOGY Baba, T., Fusaki, N., Aoyama, A., Li, D. H., Okamura, R. M., Parnes, J. R., Hozumi, N. 2005; 35 (5): 1634-1642

    Abstract

    CD72 has been reported to regulate BCR-mediated signals both positively and negatively. SHP-1 and Grb2 bind, respectively, to ITIM1 and ITIM2 of CD72. We generated transformed B cell lines with an immature phenotype following J2 virus infection of splenocytes from CD72(-/-) and wild-type (Wt) mice. The transformed lines were infected with retroviral vectors carrying Tyr (Y) to Phe (F) substitutions in the ITIM sequences (ITIM1 mutated: Y7/F; ITIM2 mutated: Y39/F; and both ITIM mutated: Y7,39/F). Cross-linking of the BCR induced growth inhibition in transfectants expressing Wt CD72, but this response was less sensitive in transfectants with Y7,39/F. The Y7/F transfectants demonstrated the least sensitive response. We were not able to obtain transfectants with Y39/F, suggesting that CD72 associated with SHP-1, but not with Grb2, delivers a strong negative signal. Pre-ligation of CD72, which induces dephosphorylation of the molecule, partially rescued the Wt transfectants from growth inhibition, leading to a growth response profile similar to that of Y7,39/F transfectants. These results suggest that ITIM1/SHP-1 delivers a very strong negative signal that is down-modulated by signals through ITIM2/Grb2, leading to delivery of an attenuated negative signal. Thus, pre-ligation of CD72 results in the manifestation of an ostensible positive signal.

    View details for DOI 10.1002/eji.200425775

    View details for Web of Science ID 000229097100033

    View details for PubMedID 15816000

  • Woodchuck interleukin-6 gene: structure,characterization, and biologic activity GENE Li, D. H., Kumanogoh, A., Cao, T. M., Parnes, J. R., Cullen, J. M. 2004; 342 (1): 157-164

    Abstract

    Woodchuck is an important animal model for studying human hepatitis B virus (HBV) infection. Within the cytokine network, interleukin-6 (IL-6) plays an important role in immune responses that may lead to viral clearance. To further understand woodchuck IL-6 biology, we cloned and characterized the IL-6 gene from white blood cells. The complete woodchuck IL-6 gene is about 7 kb and consists of five exons and four introns. The IL-6 gene organization of the woodchuck is similar to those of the human, rat, and mouse. Also several elements are highly conserved in the 300 bp promoter region of the IL-6 gene, including a nuclear factor kappa B (NF-kappaB) binding site. The woodchuck IL-6 gene encodes a polypeptide of 207 amino acids in a precursor form and 189 amino acids in the mature form. The expressed protein was 23 kDa according to SDS-PAGE. To demonstrate biologic activity, we expressed woodchuck IL-6 and showed that the purified recombinant protein induced terminal differentiation, as reflected by upregulation of Fcgamma receptor expression, and substantially inhibited proliferation of M1 cells, a murine myeloid leukemia cell line. The inhibitory effect of woodchuck IL-6 on M1 cells was blocked by an anti-gp130 monoclonal antibody, suggesting that woodchuck IL-6 activity is specifically mediated by signaling through the IL-6 receptor complex. Cloning of the woodchuck IL-6 gene and demonstrating biologic activity of the gene product will facilitate studies of human hepatitis B virus using the woodchuck model.

    View details for DOI 10.1016/j.gene.2004.07.034

    View details for Web of Science ID 000225292500018

    View details for PubMedID 15527975

  • OX52 is the rat homologue of CD6: evidence for an effector function in the regulation of CD5 phosphorylation JOURNAL OF LEUKOCYTE BIOLOGY Castro, M. A., Nunes, R. J., Oliveira, M. I., Tavares, P. A., Simoes, C., Parnes, J. R., MOREIRA, A., Carmo, A. M. 2003; 73 (1): 183-190

    Abstract

    The MRC OX52 monoclonal antibody is a marker of rat T lymphocytes. We have cloned by polymerase chain reaction the rat homologue of CD6, and fluorescein-activated cell sorter analysis and immunoprecipitations using OX52 in COS7 cells transfected with rat CD6 cDNA showed that CD6 is the cell-surface molecule recognized by OX52. Immunoprecipitation analysis showed that CD6 coprecipitated with CD5, which in turn, was coprecipitated equivalently with CD2, CD6, and the T cell receptor (TCR), but the fraction of CD5 associated with CD6 was highly phosphorylated in kinase assays, in marked contrast with the low level of phosphorylation of CD5 associated with TCR or CD2. Examination of protein kinases associating with these antigens showed that paradoxically, CD2 coprecipitated the highest amount of Lck and Fyn. CD6 also associated with Lck, Fyn, and ZAP-70, although at lower levels but additionally coprecipitated the Tec family kinase Itk, which is absent from CD2, CD5, and TCR complexes. Lck together with Itk was the best combination of kinases, effectively phosphorylating synthetic peptides corresponding to a cytoplasmic sequence of CD5. Overall, our results suggest that CD6 has an important role in the regulation of CD5 tyrosine phosphorylation, probably as a result of its unique feature of associating with kinases of different families.

    View details for DOI 10.1189/jlb.0902437

    View details for Web of Science ID 000180460900020

    View details for PubMedID 12525577

  • CD6: expression during development, apoptosis and selection of human and mouse thymocytes INTERNATIONAL IMMUNOLOGY Singer, N. G., Fox, D. A., Haqqi, T. M., Beretta, L., Endres, J. S., Prohaska, S., Parnes, J. R., Bromberg, J., Sramkoski, R. M. 2002; 14 (6): 585-597

    Abstract

    CD6, a 130-kDa surface glycoprotein, is expressed primarily on cells of T lineage. A co-stimulatory role for CD6 in mature T cells has been shown, but the function of CD6 during thymocyte development is unknown. Since CD6 ligands are expressed on thymic epithelium, their interactions with CD6 could be important in thymic selection. In this report we show that CD6 is developmentally regulated in human and mouse thymocytes, and further demonstrate that increase in the level of CD6 expression correlates with expression of the selection marker CD69. We also show that activation via CD2 induces CD6 expression on mature human thymocytes and on a subset of immature human thymocytes that are resistant to apoptosis. In human and mouse thymocytes that express heterogeneous TCR, CD6 increases occur as double-positive thymocytes are selected to a single-positive stage. In contrast, in thymocytes from TCR transgenic mice, CD6 is barely increased following selection, suggesting that as functional avidity increases, requirements for CD6-dependent co-stimulation decrease. Taken together, these results indicate that during thymic development CD6-dependent signals may contribute both to thymocyte survival, and to the overall functional avidity of selection in both man and mouse.

    View details for Web of Science ID 000175912100006

    View details for PubMedID 12039910

  • Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: A novel mechanism for regulating B cell signaling IMMUNITY Kumanogoh, A., Watanabe, C., Lee, I., Wang, X. S., Shi, W., Araki, H., Hirata, H., Iwahori, K., Uchida, J., Yasui, T., Matsumoto, M., Yoshida, K., Yakura, H., Pan, C., Parnes, J. R., Kikutani, H. 2000; 13 (5): 621-631

    Abstract

    We have identified the lymphocyte semaphorin CD100/Sema4D as a CD40-inducible molecule by subtractive cDNA cloning. CD100 stimulation significantly enhanced the effects of CD40 on B cell responses. Administration of soluble CD100 markedly accelerated in vivo antigen-specific antibody responses. CD100 receptors with different binding affinities were detected on renal tubular cells (K(d) = approximately 1 x 10(-9)M) and lymphocytes (K(d) = approximately 3 x 10(-7)M). Expression cloning revealed that the CD100 receptor on lymphocytes is CD72, a negative regulator of B cell responsiveness. CD72 thus represents a novel class of semaphorin receptors. CD100 stimulation induced tyrosine dephosphorylation of CD72 and dissociation of SHP-1 from CD72. Our findings indicate that CD100 plays a critical role in immune responses by the novel mechanism of turning off negative signaling by CD72.

    View details for Web of Science ID 000165598500005

    View details for PubMedID 11114375

  • The class IV semaphorin CD100 plays nonredundant roles in the immune system: Defective B and T cell activation in CD100-deficient mice IMMUNITY Shi, W., Kumanogoh, A., Watanabe, C., Uchida, J., Wang, X. S., Yasui, T., Yukawa, K., Ikawa, M., Okabe, M., Parnes, J. R., Yoshida, K., Kikutani, H. 2000; 13 (5): 633-642

    Abstract

    The class IV semaphorin CD100/Sema4D differentially utilizes two distinct receptors: plexin-B1 in nonlymphoid tissues, such as brain and kidney, and CD72 in lymphoid tissues. We have generated CD100-deficient mice and demonstrated that they have functional defects in their immune system, without apparent abnormalities in other tissues. The number of CD5(+) B-1 cells was considerably decreased in the mutant mice, whereas conventional B cells and T cells appeared to develop normally. In vitro proliferative responses and immunoglobulin production were reduced in CD100-deficient B cells. The humoral immune response against a T cell-dependent antigen and in vivo priming of T cells were also defective in the mutant mice. These results demonstrate nonredundant and essential roles of CD100-CD72 interactions in the immune system.

    View details for Web of Science ID 000165598500006

    View details for PubMedID 11114376

  • CD72, a negative regulator of B-cell responsiveness IMMUNOLOGICAL REVIEWS Parnes, J. R., Pan, C. 2000; 176: 75-85

    Abstract

    The ability of lymphocytes to respond to antigenic or mitogenic stimulation is regulated not only by specific receptor proteins, but also by both positive and negative regulatory proteins that set or fine-tune the threshold for responsiveness. CD72 is one such regulatory protein on B lymphocytes. It is a member of the C-type lectin superfamily and is expressed on the surface of B cells from the pro-B through the mature B-cell stage. Studies with anti-CD72 antibodies have suggested a positive regulatory role for CD72 in B-cell activation. However, the cytoplasmic tail of CD72 contains two potential immunoreceptor tyrosine-based inhibitory motifs, one of which has been shown to recruit the tyrosine phosphatase SHP- 1. These features suggest a negative regulatory role for CD72. We have generated CD72-deficient mice to elucidate the physiological role of CD72 in B-lymphocyte development and activation. Our analyses of these mice and their B-cell compartment demonstrate that CD72 is a nonredundant regulator of B-cell development and a negative regulator of B-cell responsiveness.

    View details for Web of Science ID 000089376400007

    View details for PubMedID 11043769

  • CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation IMMUNITY Pan, C., Baumgarth, N., Parnes, J. R. 1999; 11 (4): 495-506

    Abstract

    CD72, a B cell surface protein of the C-type lectin superfamily, recruits the tyrosine phosphatase SHP-1 through its ITIM motif(s). Using CD72-deficient (CD72-/-) mice, we demonstrate that CD72 is a nonredundant regulator of B cell development. In the bone marrow of CD72-/- mice, there was a reduction in the number of mature recirculating B cells and an accumulation of pre-B cells. In the periphery of CD72-/- mice, there were fewer mature B-2 cells and more B-1 cells. In addition, CD72 is a negative regulator of B cell activation, as CD72-/- B cells were hyperproliferative in response to various stimuli and showed enhanced kinetics in their intracellular Ca2+ response following IgM cross-linking.

    View details for Web of Science ID 000083343100011

    View details for PubMedID 10549631

  • Regulation of mouse CD72 gene expression during B lymphocyte development JOURNAL OF IMMUNOLOGY Ying, H., Healy, J. I., Goodnow, C. C., Parnes, J. R. 1998; 161 (9): 4760-4767

    Abstract

    CD72 is a 45-kDa transmembrane glycoprotein that is predominantly expressed on cells of the B lineage except plasma cells. Previously, we identified the 255-bp minimal mouse CD72 promoter capable of tissue-specific and developmental stage-specific expression. DNase I footprinting analysis of the 255-bp CD72 promoter revealed three protected elements, footprint (FP) I, FP II, and FP III. FP II, which extends from nucleotide -189 to -169 of the mouse CD72 promoter, exhibited both tissue-specific and developmental stage-specific activity that was reflective of the activity of the CD72 gene in vivo. In this report, we show that FP II is specifically recognized by the transcription factor B cell-specific activator protein (BSAP). Mutations eliminating the binding of BSAP in reporter constructs also eliminated the increase of reporter activity in B cells. In addition, cotransfections with reporter constructs plus different amounts of expression plasmids for BSAP showed that CD72 promoter activity was up-regulated by BSAP in plasmacytoma cells and T cells in a dose-dependent manner. Moreover, the expression level of CD72 decreased 10-fold on normal plasma cells. Compared with the presence of BSAP binding in mature B cells, the binding of BSAP was undetectable in those plasma cells. This study strongly suggests that BSAP-FP II interaction plays a critical role in determining the cell-type specificity of the CD72 promoter. The absence of positive factors such as BSAP accounts for at least part of the loss of mouse CD72 expression in plasma cells and thus might be common for the down-regulation of many molecules at the plasma cell stage.

    View details for Web of Science ID 000076581100042

    View details for PubMedID 9794407

  • Distinct stage-specific cis-active transcriptional mechanisms control expression of T cell coreceptor CD8 alpha at double- and single-positive stages of thymic development JOURNAL OF IMMUNOLOGY Zhang, X. L., Seong, R., Piracha, R., Larijani, M., Heeney, M., Parnes, J. R., Chamberlain, J. W. 1998; 161 (5): 2254-2266

    Abstract

    Developing thymocytes that give rise to CD8+ (cytotoxic) and CD4+ (helper) alpha beta-TCR T lymphocytes go through progressive stages of expression of coreceptors CD8 and CD4 from being negative for both (the double-negative stage), to coexpressing both (the double-positive (DP) stage), to a mutually exclusive sublineage-specific expression of one or the other (the single-positive (SP) stage). To delineate the mechanisms underlying regulation of CD8 during these developmental transitions, we have examined expression of a series of mouse CD8 alpha gene constructs in developing T cells of conventional and CD8 alpha "knock-out" transgenic mice. Our results indicate that cis-active transcriptional control sequences essential for stage- and sublineage-specific expression lie within a 5' 40-kb segment of the CD8 locus, approximately 12 kb upstream of the CD8 alpha gene. Studies to characterize and sublocalize these cis sequences showed that a 17-kb 5' subfragment is able to direct expression of the CD8 alpha gene up to the CD3intermediate DP stage but not in more mature DP or SP cells. These results indicate that stage-specific expression of CD8 alpha in developing T cells is mediated by the differential activity of multiple functionally distinct cis-active transcriptional control mechanisms. It will be important to determine the relationship of "switching" between these cis mechanisms and selection.

    View details for Web of Science ID 000075511600024

    View details for PubMedID 9725219

  • T cell receptor (TCR) engagement leads to activation-induced splicing of tumor necrosis factor (TNF) nuclear pre-mRNA JOURNAL OF EXPERIMENTAL MEDICINE Yang, Y., Chang, J. F., Parnes, J. R., Fathman, C. G. 1998; 188 (2): 247-254

    Abstract

    Inducible gene expression is primarily regulated at the level of transcription. Additional steps of "processing" pre-mRNA, involved in the regulation of induced gene expression, have not been previously reported. Here we report a novel mechanism of "activation-induced splicing" of preexisting tumor necrosis factor (TNF) message (pre-mRNA) in naive T lymphocytes after engagement of the T cell receptor (TCR), which still occurs after inhibition of transcription. Expression of TNF has been previously demonstrated to be regulated at both the transcriptional and translational levels. However, neither the large pool of TNF mRNA observed in activated T cells nor TNF protein production, which peaks very shortly after activation, can be solely attributed to increased transcription. Evidence is presented that activation-induced splicing of TNF pre-mRNA plays a significant role in the rapid production of TNF seen in activated T cells. Activation triggers processing of TNF pre-mRNA that has accumulated in naive T cells (before activation-induced transcription), and the mature TNF mRNA is translocated to the cytoplasm for rapid translation and protein production. This novel form of activation-induced splicing of TNF may allow T cells to mount an immediate response to activation stimuli under physiological conditions.

    View details for Web of Science ID 000075236900003

    View details for PubMedID 9670037

  • Mechanisms of CD8 beta-mediated T cell response enhancement: Interaction with MHC class I beta(2)-microglobulin and functional coupling to TCR/CD3 JOURNAL OF IMMUNOLOGY Wheeler, C. J., Chen, J. Y., Potter, T. A., Parnes, J. R. 1998; 160 (9): 4199-4207

    Abstract

    CD8beta expression results in enhanced IL-2 production and/or altered specificity in allogeneic MHC class I-restricted T cell hybridomas. Expression of chimeric CD8beta-alpha molecules (extracellular CD8beta, transmembrane and cytoplasmic CD8alpha) also results in enhancement of T hybridoma responses to alloantigen, suggesting that at least part of CD8beta's ability to influence responses similar to those of mature CD8+ T cells is mediated by its extracellular domain. Current data suggest that CD8beta-mediated response enhancement proceeds through mechanisms similar to those mediated by CD8alpha, i.e., interacting with MHC class I and stabilizing CD8-associated Lck activity. In this study we present evidence that the extracellular portion of CD8beta is capable of independent interaction with MHC class I/beta2m dimers in the absence of CD8alpha. In addition, CD8beta may enhance interaction with MHC class I/beta2m when associated with CD8alpha. We also present evidence from T hybridoma responses suggesting that the extracellular portion of CD8beta is uniquely capable of efficient interaction with the TCR/CD3 complex and may couple the TCR/CD3 complex to other surface components capable of enhancing TCR-mediated signals. This represents the first evidence that a critical coreceptor function can be preferentially associated with the CD8beta subunit.

    View details for Web of Science ID 000073225800010

    View details for PubMedID 9574520

  • PU.1/Spi-1 is essential for the B cell-specific activity of the mouse CD72 promoter JOURNAL OF IMMUNOLOGY Ying, H., Chang, J. F., Parnes, J. R. 1998; 160 (5): 2287-2296

    Abstract

    CD72 is a 45-kDa glycoprotein that is predominantly expressed on cells of the B lineage, except for plasma cells. Its expression pattern is representative of many B cell-specific proteins, which are essential for B cell development and activation but are down-regulated after B cells become terminally differentiated plasma cells. We have examined the promoter region of the mouse CD72 gene to identify sequences responsible for this regulatory pattern. The CD72 gene does not have an obvious TATAA box. Primer extension assays identified multiple transcription initiation sites. Deletion analyses have identified the 255-bp minimal promoter required for tissue-specific and developmental stage-specific expression. DNase I footprinting analysis of the CD72 minimal promoter revealed three protected elements: FP I, FP II, and FP III. Sequences corresponding to FP I or III gave increased reporter gene activity specifically in B cells, but not in T cells or NIH-3T3 cells. Sequences corresponding to FP II gave increased reporter gene activity in mature B cells, but not in plasma cells or non-B cells. Electrophoretic mobility shift assays and DNase I protection analyses revealed that FP I was bound by the transcription factor PU.1/Spi-1. Transient reporter analyses with plasmid bearing the mutated PU.1 binding site showed that binding of PU.1 is necessary for the increase in CD72 promoter activity in B cells. These results suggest that the 255-bp CD72 promoter confers both tissue specificity and developmental stage specificity, and that the B cell and macrophage-specific transcription factor PU.1 is essential for regulating the tissue specificity of the mouse CD72 promoter.

    View details for Web of Science ID 000072115700033

    View details for PubMedID 9498769

  • The level of CD4 surface protein influences T cell selection in the thymus JOURNAL OF IMMUNOLOGY Frank, G. D., Parnes, J. R. 1998; 160 (2): 634-642

    Abstract

    During T cell development thymocytes are subjected to positive and negative selection criteria to ensure that the mature T cell repertoire is MHC restricted, yet self tolerant at the same time. The CD4 and CD8 coreceptors are thought to play a crucial role in this developmental process. To elucidate the role of CD4 in T cell selection, we have produced a mouse strain that expresses CD4 at a reduced level. We used homologous recombination in embryonic stem cells to insert neo into the 3' untranslated region of CD4. The resulting mice have a reduction in the percentage of CD4+ cells in the thymus and a concomitant increase in CD8+ cells. In addition, breeding two individual class II-restricted TCR transgenic mice onto the CD4low (low level of CD4) mutant background affects the selection of each TCR differentially. In one case (AND TCR transgenic), significantly fewer CD4+ cells with the transgenic TCR develop on the CD4low mutant background, whereas in the other (5C.C7 TCR transgenic), selection to the CD4 lineage is only slightly reduced. These data support the differential avidity model of positive and negative selection. With little or no avidity, the cell succumbs to programmed cell death, low to moderate avidity leads to positive selection, and an avidity above a certain threshold, presumably above one that would lead to autoreactivity in the periphery results in clonal deletion. These data also support the idea that a minimum avidity threshold for selection exists and that CD4 plays a crucial role in determining this avidity.

    View details for Web of Science ID 000071915200015

    View details for PubMedID 9551897

  • Specific demethylation of the CD4 gene during CD4 T lymphocyte differentiation MOLECULAR IMMUNOLOGY LANDOLFI, M. M., Scollay, R., Parnes, J. R. 1997; 34 (1): 53-61

    Abstract

    The expression of CD4 during T cell development is a highly regulated process. Numerous regulatory elements have been identified including a promoter, two distinct enhancers and a silencer. Here we report a methylation site in the first intron of the CD4 gene that is specifically demethylated in cells which have previously, or are currently expressing CD4. In addition, this site becomes progressively demethylated as T lymphocytes differentiate from double-negative to double-positive to CD4 single-positive thymocytes, and finally to CD4 single-positive peripheral T lymphocytes. This specific and progressive demethylation suggests that this site represents another potential control region for the regulation of CD4.

    View details for Web of Science ID A1997XC15000006

    View details for PubMedID 9182876

  • Allele-specific expression of the mouse B-cell surface protein CD72 on T cells IMMUNOGENETICS Robinson, W. H., LANDOLFI, M. M., Parnes, J. R. 1997; 45 (3): 195-200

    Abstract

    CD72 is a 45 000 Mr mouse B-cell surface glycoprotein involved in B-cell proliferation and differentiation. Expression of mouse CD72 is thought to be restricted to the B-cell lineage. We recently demonstrated that the monoclonal antibodies K10.6 and B9.689, previously defined as recognizing the mouse lymphocyte alloantigens Ly-19.2 and Ly-32.2, respectively, recognize specific alleles of CD72. Early studies using antibody-mediated cytotoxicity assays demonstrated that K10.6 and B9.689 react with B cells, several T-cell lines, and a subset of peripheral T cells. These findings led us to consider the possibility that CD72 might also be expressed on a subset of T cells. In this report we demonstrate that CD72 is constitutively expressed on a fraction of peripheral T cells isolated from strains of mice expressing the CD72(b) allele, but not the CD72(a) or CD72(c) alleles. Three days after activating T cells with concanavalin A or plate-bound CD3-specific mAb, CD72 is expressed on a larger fraction of peripheral T cells as well as a fraction of thymocytes from mouse strains expressing the CD72(b) allele. CD72 is expressed on both the CD4(+) and CD8(+) thymocyte and peripheral T-cell subsets. No CD72 expression is detected on activated thymocytes or peripheral T cells from mouse strains expressing the CD72(a) or CD72(c) alleles. Expression of CD72(b) on peripheral T cells was confirmed by northern blot analysis demonstrating CD72 mRNA expression. These results demonstrate that CD72 expression is not restricted to B lineage cells in mouse strains expressing the CD72(b) allele; instead, a population of T lineage cells in these mice also expresses CD72.

    View details for Web of Science ID A1997WE19000005

    View details for PubMedID 8995186

  • Molecular linkage of the mouse CD5 and CD6 genes IMMUNOGENETICS LECOMTE, O., Bock, J. B., Birren, B. W., Vollrath, D., Parnes, J. R. 1996; 44 (5): 385-390

    View details for Web of Science ID A1996VG28500009

    View details for PubMedID 8781125

  • IDENTIFICATION OF A MOUSE PROTEIN HOMOLOGOUS TO THE HUMAN CD6 T-CELL SURFACE PROTEIN AND SEQUENCE OF THE CORRESPONDING CDNA JOURNAL OF IMMUNOLOGY Robinson, W. H., Prohaska, S. S., Santoro, J. C., Robinson, H. L., Parnes, J. R. 1995; 155 (10): 4739-4748

    Abstract

    CD6 is a 105/130 kDa monomeric T cell surface glycoprotein that has been shown to play a role in human T cell activation. Recently a partial mouse CD6 cDNA sequence was described. We have isolated full-length cDNA clones including the initiation codon and sequence encoding the full signal peptide, as well as an additional 39 amino acids within the cytoplasmic domain as compared to the previously reported clone. The predicted full-length mouse CD6 protein contains 665 amino acids and has the features of a type I integral membrane protein. The extracellular domain of mouse CD6 is composed of three repeated cysteine-rich domains similar to those in human CD6, mouse and human CD5, and other members of a family of proteins whose prototype is the type I macrophage scavenger receptor. In marked contrast to the previously published human CD6 sequence, the mouse sequence predicts a long cytoplasmic tail that is not closely related to other proteins and possesses two proline-rich motifs containing the SH3-domain binding consensus sequence, three protein kinase C phosphorylation site motifs, nine casein kinase-2 phosphorylation site motifs, and a serine-threonine-rich motif repeated three times. Northern blot analysis revealed that mouse CD6 mRNA is expressed predominantly in thymus, lymph node, and spleen. A polyclonal antiserum was raised against mouse CD6 by gene gun plasmid DNA immunization of rabbits with the mouse CD6 cDNA in an expression vector. In immunofluorescence analysis this polyclonal antiserum positively stained the surface of cells transfected with the mouse CD6 cDNA in an expression vector, as well as most normal mouse thymocytes and peripheral T cells. CD6 protein is expressed on most CD4+CD8+ double-positive and CD4+ or CD8+ single-positive thymocytes, and is expressed at highest levels on mature CD3high thymocytes. The expression of mouse CD6 in thymocytes and peripheral T cells correlates closely with the expression of the related CD5 molecule. The polyclonal rabbit anti-mouse CD6 Abs immunoprecipitated a major polypeptide of 128 kDa from resting and 130 kDa from PMA- and FCS-activated mouse thymocytes and lymph node cells; it is likely that this increase in size upon activation is due to phosphorylation of mouse CD6 as has been described for human CD6. These data demonstrate that mouse thymocytes and T cells express a 130-kDa cell surface protein homologous to human CD6.

    View details for Web of Science ID A1995TD88800029

    View details for PubMedID 7594475

  • HUMAN CD6 POSSESSES A LARGE, ALTERNATIVELY SPLICED CYTOPLASMIC DOMAIN EUROPEAN JOURNAL OF IMMUNOLOGY Robinson, W. H., DEVEGVAR, H. E., Prohaska, S. S., Rhee, J. W., Parnes, J. R. 1995; 25 (10): 2765-2769

    Abstract

    Human CD6 is a monomeric 105/130-kDa T cell surface glycoprotein that is involved in T cell activation. The apparent discrepancy between the size of the cytoplasmic domain in human (44 amino acids) and mouse (243 amino acids) CD6, led us to use reverse transcriptase-polymerase chain reaction of human peripheral blood lymphocyte mRNA to isolate cDNA clones that include the carboxyl-terminal coding region of human CD6. The nucleotide sequence of the longest human cDNA clone, CD6-PB1, predicts a protein of 668 amino acids with a 244-amino acid cytoplasmic domain similar in size to and possessing 71.5% amino acid sequence identity with the cytoplasmic domain of mouse CD6. This previously unrecognized 244-amino acid cytoplasmic domain does not have significant homology to any other known protein (except mouse CD6), but does possess two proline-rich motifs containing the SH3 domain-binding consensus sequence, a serine-threonine-rich motif repeated three times, three protein kinase C phosphorylation-site motifs, and 10 casein kinase-2 phosphorylation-site motifs. These sequences are likely to play a role in the ability of CD6-specific monoclonal antibodies to stimulate T cell proliferation. Full-length CD6 cDNA containing this cytoplasmic domain sequence encodes a monomeric 105/130-kDa protein that can be immunoprecipitated from the surface of transfected cells and comigrates upon SDS-PAGE with wild-type CD6 immunoprecipitated from PBL. We also isolated two alternatively spliced forms of human CD6 cDNA lacking sequences encoding membrane-proximal regions of the cytoplasmic domain which maintain the same reading frame as CD6-PB1. The short cytoplasmic domain of the previously reported human CD6-15 cDNA clone results from a deletion of a 20-bp segment through use of an alternative 3' splice site, resulting in a frame shift and premature termination of translation relative to the clones we have isolated. These data demonstrate that human CD6 possesses a large cytoplasmic domain containing sequence motifs that are likely to be involved in signal transduction upon stimulation of T cells through CD6 ligation.

    View details for Web of Science ID A1995TB37100007

    View details for PubMedID 7589069

  • STRUCTURE OF THE MOUSE CD72 (LYB-2) GENE AND ITS ALTERNATIVELY SPLICED TRANSCRIPTS JOURNAL OF IMMUNOLOGY Ying, H., Nakayama, E., Robinson, W. H., Parnes, J. R. 1995; 154 (6): 2743-2752

    Abstract

    The complete sequence of the CD72 gene from the C57L mouse, including the 5' and 3' flanking sequences, is reported. The gene spans 6830 base pairs and includes nine exons surrounding eight introns. It does not have an obvious TATAA box, so it belongs to a group of genes with TATA-less promoters that are regulated during mammalian immunodifferentiation. cDNA sequence comparisons among CD72a, CD72b, and CD72c alleles have demonstrated two distinct seven amino acid insertion/deletions among these allelic variants. Based on our genomic sequence studies as well as PCR analyses, we found that different strains of mice can alternatively or exclusively use either of two AG sites surrounding the 21-bp insertion/deletions as 3' splice sites in an allele-specific manner. Other alternative splicing events, such as exon skipping, also contribute to CD72 polymorphism. In mouse splenic B cells there are allele-specific distributions of CD72 mRNAs that contain sequences from both exon 3 and exon 4, from either exon 3 or exon 4, or from neither exon 3 nor 4. It is unclear what the in vivo function might be of the proteins encoded by the mRNA forms lacking these exon sequences.

    View details for Web of Science ID A1995QL08400021

    View details for PubMedID 7876545

  • CD4 and CD8 in T cell lineage commitment: alterations induced by expression of a CD8/CD4 chimeric transgene. Seminars in immunology Parnes, J. R., Seong, R. H. 1994; 6 (4): 221-229

    Abstract

    The mechanism by which thymocytes expressing both the CD4 and CD8-coreceptor proteins differentiate into mature T cells expressing either CD4 or CD8 is not well understood. We have shown that expression of a chimeric CD8/CD4 transgene can alter T cell lineage commitment such that cells expressing a transgenic class I major histocompatibility complex-restricted T cell receptor can differentiate to the CD4 rather than those the CD8 lineage. The implications of these findings and those of others for existing instructive and stochastic models of thymocyte lineage commitment are discussed, and an alternative model is considered.

    View details for PubMedID 8000031

  • BIOCHEMICAL IDENTITY OF THE MOUSE LY-19.2 AND LY-32.2 ALLOANTIGENS WITH THE B-CELL DIFFERENTIATION ANTIGEN LYB-2/CD72 JOURNAL OF IMMUNOLOGY Robinson, W. H., LANDOLFI, M. M., Schafer, H., Parnes, J. R. 1993; 151 (9): 4764-4772

    Abstract

    Lyb-2/CD72 is a 45-kDa mouse B cell surface protein that binds CD5 (Ly-1) and has been shown to induce B cell proliferation upon mAb binding. The serologically defined Ly-19.2 and Ly-32.2 lymphocyte alloantigens have mouse strain distribution patterns similar to that of the Lyb-2/CD72 alleles and map to the same region on chromosome 4 as Lyb-2/CD72. Our recent isolation of the Lyb-2a, -2b, and -2c cDNA has enabled us in this report to examine the relationship between Ly-19, Ly-32, and Lyb-2/CD72. A rat T cell line transfected with a mouse Lyb-2a cDNA is recognized by Ly-19.2-specific mAb, whereas transfectants expressing the Lyb-2b cDNA are recognized by both Ly-19.2 and Ly-32.2-specific mAb. Cell surface iodination immunoprecipitation analysis from Lyb-2a cDNA transfectants using Lyb-2a- and Ly-19.2-specific mAb as well as from Lyb-2b cDNA transfectants using Lyb-2b-, Ly-19.2-, and Ly-32.2-specific Ab, produced immunoprecipitates containing comigrating 45-kDa polypeptides. Preclearing studies with these transfectants indicate that the immunoprecipitated proteins represent the same polypeptide chain. These results demonstrate that the mouse Ly-19.2 and Ly-32.2 alloantigens are in fact the B cell differentiation Ag Lyb-2/CD72.

    View details for Web of Science ID A1993MD34900035

    View details for PubMedID 8409435

  • CD2(-)CD4(-)CD8(-) LYMPH-NODE T-LYMPHOCYTES IN MRL LPR LPR MICE ARE DERIVED FROM A CD2(+)CD4(+)CD8(+) THYMIC PRECURSOR JOURNAL OF IMMUNOLOGY LANDOLFI, M. M., VanHouten, N., Russell, J. Q., Scollay, R., Parnes, J. R., Budd, R. C. 1993; 151 (2): 1086-1096

    Abstract

    MRL lpr/lpr (lymphoproliferative, lpr) mice demonstrate an age-dependent lymphoproliferation and development of autoimmunity. Characteristic of the lymphoproliferation in these mice is the accumulation of large numbers of CD4-CD8-(CD4-8-),CD3+ T lymphocytes in their lymph nodes. The development of the CD4-8- cells, which also aberrantly express B220 and CD44 (Pgp-1) but are CD2-, has been shown to be thymus dependent. An unusual feature of lpr CD4-8-T lymphocytes is that although they appear unresponsive to stimulation, as defined by proliferation and IL-2 production, they have undergone thymic negative selection. As thymic deletion normally occurs at the CD4+CD8+ (CD4+8+) stage, this raises the dilemma that lpr CD4-8- T lymphocytes have either previously been CD4+8+, or they are able to undergo thymic selection as CD4-8- cells. We have addressed this question by examining the methylation status of the CD8 gene in MRL lpr CD4-8- lymph node cells. Demethylation of the CD8 gene has been shown to be an indicator of previous CD8 expression. We find that the CD8 gene in lpr CD4-8- lymph node cells, as well as in the abnormal B220+ CD4-8- lpr thymocytes, is demethylated, suggesting that these cells have previously expressed CD8. In addition, we find that the lpr CD4+8+ thymocyte population contains an increased percentage of atypical B220+, CD44+ cells that are virtually all CD2+. Taken together, these data are consistent with the lpr CD2-CD4-8- population of LNC having arisen from a CD2+ CD4+8+ thymic stage of differentiation.

    View details for Web of Science ID A1993LN98600054

    View details for PubMedID 7687614

  • ROLE OF CD4 AND CD8 IN T-CELL ACTIVATION AND DIFFERENTIATION ADVANCES IN IMMUNOLOGY, VOL 53 Miceli, M. C., Parnes, J. R. 1993; 53: 59-122

    View details for Web of Science ID A1993BZ73D00003

    View details for PubMedID 8512039

  • POLYMORPHIC SPECIFICITY OF Q1/28, A MONOCLONAL-ANTIBODY THAT PREFERENTIALLY REACTS WITH FREE CLASS-I HEAVY-CHAINS IMMUNOGENETICS Benjamin, R. J., Abrams, J. R., Parnes, J. R., Madrigal, J. A., Parham, P. 1992; 37 (1): 73-76

    View details for Web of Science ID A1992JV60900010

    View details for PubMedID 1428015

  • EXTENSIVE POLYMORPHISM IN THE EXTRACELLULAR DOMAIN OF THE MOUSE B-CELL DIFFERENTIATION ANTIGEN LYB-2/CD72 JOURNAL OF IMMUNOLOGY Robinson, W. H., Ying, H., Miceli, M. C., Parnes, J. R. 1992; 149 (3): 880-886

    Abstract

    Lyb-2/CD72 is a 45-kDa mouse B cell surface protein that binds CD5 and has been shown to play a role in B cell proliferation and differentiation. Using the polymerase chain reaction we have isolated and sequenced cDNA clones encoding the serologically defined mouse Lyb-2a, Lyb-2b, and Lyb-2c alleles. We confirmed that our full length cDNA clones encode the Lyb-2a, -2b, and -2c alleles, respectively, by transfecting the isolated Lyb-2/CD72 cDNA clones into L cells and demonstrating that the transfectants bind only the appropriate allele specific anti-Lyb-2/CD72 antibodies. Sequence comparisons demonstrate that the Lyb-2/CD72 allels are highly conserved in their cytoplasmic and transmembrane domains but exhibit a high degree of polymorphism in their extracellular domains. This polymorphism in the extracellular region involves amino acid substitutions at a minimum of 20 residues and is concentrated primarily in the membrane distal region. cDNA sequence comparisons also demonstrate two distinct seven amino acid insertion/deletions among these allelic variants. A form of Lyb-2b cDNA lacking the sequence encoding the transmembrane region was isolated from a C57B1/6 mouse and a CH12.LX subline. The Lyb-2/CD72 PCR products from mRNA of mice expressing Lyb-2a and Lyb-2c contain a DNA fragment that corresponds in size to the transmembraneless form, suggesting that these mouse strains also express this mRNA.

    View details for Web of Science ID A1992JF47400019

    View details for PubMedID 1634777

  • AN IMMUNOLOGICAL ROLE FOR THE CD8 BETA-CHAIN NATURE Wheeler, C. J., VONHOEGEN, P., Parnes, J. R. 1992; 357 (6375): 247-249

    Abstract

    Mature T cells can be functionally divided into two categories distinguished by surface expression of either CD4 or CD8, which in turn corresponds to restriction by and binding to class II or class I major histocompatibility complex proteins, respectively. CD8 can be expressed as a homodimer of the alpha-chain, or as a heterodimer of alpha- and beta-chains on human and mouse T cells, although most peripheral T cells seem to express CD8 alpha beta heterodimers exclusively (reviewed in ref. 9). Functional characterization of CD8 has focused primarily on the effect of the alpha-chain, which enhances or reconstitutes T-cell responses in homodimeric form and may play a specific role in thymic selection. In contrast, no role has been ascribed to CD8 beta or alpha beta heterodimers specifically. Here we show that CD8 alpha beta transfectants produce more interleukin-2 than CD8 alpha transfectants in response to specific stimuli. Increased interleukin-2 is also observed in cells expressing hybrid CD8 beta-alpha molecules (extracellular CD8 beta plus CD8 alpha transmembrane and cytoplasmic regions) on their surface. These results indicate that external portions of CD8 beta could be critical and that they may act independently of CD8 alpha in mediating their augmentation effect.

    View details for Web of Science ID A1992HV19500056

    View details for PubMedID 1534146

  • SIGNAL FOR T-CELL DIFFERENTIATION TO A CD4 CELL LINEAGE IS DELIVERED BY CD4 TRANSMEMBRANE REGION AND OR CYTOPLASMIC TAIL NATURE Seong, R. H., Chamberlain, J. W., Parnes, J. R. 1992; 356 (6371): 718-720

    Abstract

    Mature T cells express either CD4 or CD8 on their surface. Most helper T cells express CD4, which binds to class II major histocompatibility complex (MHC) proteins, and most cytotoxic T cells express CD8, which binds to class I MHC proteins. In the thymus, mature CD4+CD8- and CD4-CD8+ T cells expressing alpha beta T-cell antigen receptors (TCR) develop from immature thymocytes through CD4+CD8+ alpha beta TCR+ intermediates. Experiments using mice transgenic for alpha beta TCR suggest that the specificity of the TCR determines the CD4/CD8 phenotype of mature T cells. These results, however, do not indicate how a T cell differentiates into the CD4 or CD8 lineage. Here we show that the CD4 transmembrane region and/or cytoplasmic tail mediates the delivery of a specific signal that directs differentiation of T cells to a CD4 lineage. We generated transgenic mice expressing a hybrid molecule composed of the CD8 alpha extracellular domains linked to the CD4 transmembrane region and cytoplasmic tail. We predicted that this hybrid molecule would bind to class I MHC proteins through the extracellular domains but deliver the intracellular signals characteristic of CD4. By crossing our transgenic mice with mice expressing a transgenic alpha beta TCR specific for a particular antigen plus class I MHC protein, we were able to express the hybrid molecule in developing thymocytes expressing the class I MHC-restricted TCR. Our results show that the signal transduced by the hybrid molecule results in the differentiation of immature thymocytes expressing a class I-restricted TCR into mature T cells expressing CD4.

    View details for Web of Science ID A1992HQ14600063

    View details for PubMedID 1533274

  • IDENTITY OF HUMAN LYB-2 AND CD72 AND LOCALIZATION OF THE GENE TO CHROMOSOME-9 EUROPEAN JOURNAL OF IMMUNOLOGY VONHOEGEN, I., Hsieh, C. L., SCHARTING, R., FRANCKE, U., Parnes, J. R. 1991; 21 (6): 1425-1431

    Abstract

    We have recently reported the isolation of cDNA clones encoding the human homolog of the mouse B cell differentiation antigen Lyb-2. Expression of Lyb-2 is restricted to B lineage cells and turned off in antibody-secreting plasma cells in both mice and humans. Functional studies with anti-mouse Lyb-2 monoclonal antibodies (mAb) suggest that this protein may be involved in signals for B cell proliferation. We now describe the generation of mAb specific for human Lyb-2. Furthermore, we demonstrate that the human Lyb-2 protein is recognized by a mAb specific for the newly clustered pan B cell surface antigen CD72, which had been defined by mAb. Mouse L(tk-) cells expressing a transfected cDNA encoding human Lyb-2 bind a mAb specific for CD72. We further show that an antiserum and a mAb specific for human Lyb-2 and an anti-CD72 mAb immunoprecipitate the identical protein from human splenic B cells and B cell lines, as well as from transfected L(tk-) cells. These data indicate that CD72 is the human equivalent of mouse Lyb-2. We have additionally localized the gene for human Lyb-2/CD72 on the short arm of chromosome 9. Mouse Lyb-2 had been previously mapped to mouse chromosome 4. Lyb-2/CD72 is now the tenth gene known to be localized on human chromosome 9 and mouse chromosome 4.

    View details for Web of Science ID A1991FT00500014

    View details for PubMedID 2044654

  • The roles of CD4 and CD8 in T cell activation. Seminars in immunology Miceli, M. C., Parnes, J. R. 1991; 3 (3): 133-141

    Abstract

    CD4 and CD8 T cell surface molecules play a role in T cell recognition and activation by binding to their respective class II and class I major histocompatibility complex (MHC) ligands on an antigen presenting cell (APC). Though CD4 and CD8 are capable of binding to MHC molecules in the absence of the T cell receptor (TCR), increasing evidence suggests that they may primarily function by complexing with the TCR to form a 'co-receptor' for recognition of antigen-bound MHC. Using gene transfer studies we have demonstrated that CD4 and CD8 can augment antigen-induced IL-2 production through different mechanisms dependent on whether or not they can bind MHC independently of the TCR or complexed with the TCR. Under circumstances where CD4 and CD8 can bind to the same MHC ligand as the TCR, they potentiate antigen-induced IL-2 production maximally by a mechanism in large part dependent on their cytoplasmic tails. Enhancement of antigen-induced IL-2 production can also occur under circumstances where CD4 and CD8 bind on MHC ligand distinct from that recognized by the TCR. In this instance, the magnitude of this enhancement is not as great and appears (at least for CD8) to be independent of the cytoplasmic tail and the associated p56lck. The dependence of co-receptor function on the cytoplasmic tail of CD4 or CD8 may reflect the activity of the associated intracellular tyrosine kinase p56lck.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for PubMedID 1909592

  • ADHESION VERSUS CORECEPTOR FUNCTION OF CD4 AND CD8 - ROLE OF THE CYTOPLASMIC TAIL IN CORECEPTOR ACTIVITY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Miceli, M. C., VONHOEGEN, P., Parnes, J. R. 1991; 88 (7): 2623-2627

    Abstract

    CD4 and CD8 play an important role in T-cell recognition and activation; however, their mechanisms of action are not well understood. We compare the effects of expressing CD4 and CD8 alpha either individually or together in a class II-restricted T-cell hybridoma. We also compare the effects of expressing truncated forms of CD4 or CD8 alpha that do not have a cytoplasmic tail and thus do not associate with the T-cell-specific tyrosine kinase p56lck, which has been implicated in T-cell activation. We demonstrate that, although CD4 and CD8 alpha can specifically enhance interleukin 2 secretion, maximal potentiation occurs with expression of CD4, which, unlike CD8, can bind to the same major histocompatibility complex protein as the T-cell receptor. Our data further indicate that the cytoplasmic tail and/or the associated p56lck are primarily significant for interleukin 2 secretion by the hybridomas we have examined when CD4 or CD8 can bind to the same major histocompatibility complex ligand as the T-cell receptor.

    View details for Web of Science ID A1991FE86400003

    View details for PubMedID 1901411

  • IDENTIFICATION OF A HUMAN PROTEIN HOMOLOGOUS TO THE MOUSE LYB-2 B-CELL DIFFERENTIATION ANTIGEN AND SEQUENCE OF THE CORRESPONDING CDNA JOURNAL OF IMMUNOLOGY VONHOEGEN, I., Nakayama, E., Parnes, J. R. 1990; 144 (12): 4870-4877

    Abstract

    We have isolated and sequenced cDNA clones encoding the human homolog of the mouse Lyb-2 B cell differentiation Ag. Previous data suggest that Lyb-2 might represent a growth factor or lymphokine receptor. Human Lyb-2 mRNA is expressed in normal human tonsils and bone marrow cells, in the pre-B cell line REH, in three Burkitt lymphoma cell lines, and in some EBV-transformed B cell lines, but not in antibody-secreting myeloma cell lines, T cell lines, or a promyelocytic leukemia cell line. These data indicate that expression of human Lyb-2 is restricted to B lineage cells and turned off in antibody-secreting plasma cells. A polyclonal mouse antiserum was raised against human Lyb-2 and immunoprecipitates a Mr 42,000 protein from REH, Raji, and Daudi cells and from mouse L(tk) cells transfected with the human Lyb-2 cDNA in an expression vector. The human Lyb-2 protein is related to both the asialoglycoprotein receptor and CD23, the B cell-specific FcR for IgE. These data demonstrate that human B cells express a previously undescribed cell surface protein that is homologous to mouse Lyb-2 and has a similar pattern of expression during B cell development.

    View details for Web of Science ID A1990DK40600054

    View details for PubMedID 2141045

  • EQUIVALENCE OF HUMAN AND MOUSE CD4 IN ENHANCING ANTIGEN RESPONSES BY A MOUSE CLASS-II-RESTRICTED T-CELL HYBRIDOMA JOURNAL OF EXPERIMENTAL MEDICINE VONHOEGEN, P., Miceli, M. C., Tourvieille, B., Schilham, M., Parnes, J. R. 1989; 170 (6): 1879-1886

    Abstract

    We have examined the ability of hCD4 to interact functionally with mouse class II MHC molecules using the mouse T cell hybridoma BI-141, specific for beef insulin. We have previously shown that expression of mouse CD4 results in a marked enhancement of IL-2 release by BI-141 cells in response to beef insulin or, in a cross-reactive response, to pork insulin, on the appropriate mouse APCs. We now demonstrate that expression of hCD4 results in an equivalent stimulation of antigen responses by this mouse T cell hybridoma. The specificity of this effect was demonstrated by mAb and gp120 blocking studies. These data provide the first direct evidence for function of hCD4 and in an exclusively mouse system.

    View details for Web of Science ID A1989CD27200007

    View details for PubMedID 2685171

  • SEQUENCE OF THE LYB-2 B-CELL DIFFERENTIATION ANTIGEN DEFINES A GENE SUPERFAMILY OF RECEPTORS WITH INVERTED MEMBRANE ORIENTATION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nakayama, E., VONHOEGEN, I., Parnes, J. R. 1989; 86 (4): 1352-1356

    Abstract

    Lyb-2 is a mouse B-cell differentiation antigen expressed on the surface of pre-B cells and B cells but not on terminally differentiated antibody-secreting plasma cells. Lyb-2 has been shown to play a role in B-cell activation and differentiation and may be a receptor for a B-cell growth factor or lymphokine. We have isolated and sequenced cDNA encoding the Lyb-2.1 allele. Lyb-2 mRNA is expressed only in B-lineage cells and is absent from antibody-secreting cell lines. The predicted protein contains 354 amino acids and is lacking an amino-terminal signal peptide. The protein is shown to be oriented with its carboxyl terminus external to the cell. Sequence comparisons demonstrate that Lyb-2 is homologous to the asialoglycoprotein receptor and to CD23, the B-cell-specific Fc receptor for IgE, both of which are oriented with their carboxyl termini external to the cell. These molecules, therefore, constitute a gene superfamily of cell surface receptors with inverted membrane orientation.

    View details for Web of Science ID A1989T274500055

    View details for PubMedID 2645579

  • MOLECULAR-BIOLOGY AND FUNCTION OF CD4 AND CD8 ADVANCES IN IMMUNOLOGY Parnes, J. R. 1989; 44: 265-311

    View details for Web of Science ID A1989U769700006

    View details for PubMedID 2493728

  • ROLE OF CD4 AND CD8 IN ENHANCING T-CELL RESPONSES TO ANTIGEN COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY Parnes, J. R., VONHOEGEN, P., Miceli, M. C., Zamoyska, R. 1989; 54: 649-655

    View details for Web of Science ID A1989JX74600005

    View details for PubMedID 2518008

  • GENES ENCODING T-CELL ANTIGENS ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Parnes, J. R. 1988; 546: 109-115

    View details for Web of Science ID A1988DE24700013

    View details for PubMedID 3073690

  • A 2ND CHAIN OF HUMAN CD8 IS EXPRESSED ON PERIPHERAL-BLOOD LYMPHOCYTES JOURNAL OF EXPERIMENTAL MEDICINE Shiue, L., GORMAN, S. D., Parnes, J. R. 1988; 168 (6): 1993-2005

    Abstract

    Human CD8 has been thought to consist of disulfide-linked homodimers and homomultimers of a single polypeptide chain homologous to mouse and rat CD8 alpha. In contrast, mouse and rat CD8 are composed of disulfide-linked heterodimers of alpha and beta chains. We have now isolated and sequenced cDNA clones encoding a human homologue of mouse and rat CD8 beta. One such clone was inserted into an expression vector and its encoded product was shown to be expressed on the cell surface after cotransfection into L cells with the human CD8 alpha gene. A second form of human CD8 beta cDNA encoding a protein with an altered cytoplasmic tail was similarly transfected, but its product could not be demonstrated on the cell surface. CD8 beta was further shown to be expressed on the surface of almost all CD8+ human peripheral blood T cells. These data provide the first evidence that human CD8 is a heterodimeric protein.

    View details for Web of Science ID A1988R362000004

    View details for PubMedID 3264320

  • A CD8 POLYPEPTIDE THAT IS LOST AFTER PASSING THE GOLGI BUT BEFORE REACHING THE CELL-SURFACE - A NOVEL SORTING MECHANISM EMBO JOURNAL Zamoyska, R., Parnes, J. R. 1988; 7 (8): 2359-2367

    Abstract

    The murine CD8 T cell differentiation antigen is a glycoprotein expressed on the cell surface as a heterodimer comprising the products of two closely linked genes, Ly-2 and Ly-3. The Ly-2 gene encodes, through a mechanism of alternate splicing, two polypeptide chains, alpha and alpha', that differ from one another in the lengths of their cytoplasmic tails. All T cells transcribe and translate both the alpha and alpha' polypeptides of Ly-2 and form heterodimers of each of these polypeptides disulphide-bonded with the Ly-3 polypeptide. However, there is very specific, developmentally controlled regulation of the expression of these heterodimers on the cell surface. Namely, immature T cells show no discrimination of CD8 molecules and express on their cell surface heterodimers containing the Ly-3 polypeptide linked to either the alpha or alpha' chain of Ly-2. In contrast, mature T cells express on their cell surface predominantly the heterodimer containing the Ly-2 alpha chain, the species which has a cytoplasmic tail. Moreover, in mature T cells the complexes which contain the alpha' chain are retained within the cell late in processing. These data emphasize the importance of the CD8 accessory molecule in the development of the functional T cell repertoire and uncover a novel protein sorting mechanism in mature T cells.

    View details for Web of Science ID A1988P464000011

    View details for PubMedID 3263917

  • RESCUE OF DAUDI CELL HLA EXPRESSION BY TRANSFECTION OF THE MOUSE BETA-2-MICROGLOBULIN GENE JOURNAL OF EXPERIMENTAL MEDICINE Seong, R. H., CLAYBERGER, C. A., KRENSKY, A. M., Parnes, J. R. 1988; 167 (2): 288-299

    Abstract

    The Daudi cell line is a B-lymphoblastoid line derived from a Burkitt lymphoma. Daudi cells lack cell surface expression of class I HLA molecules despite the presence of intracellular class I heavy chains. They have a defect in the gene encoding beta 2-microglobulin (beta 2m), resulting in lack of translatable mRNA for this protein. It has been thought that this deficiency is responsible for the lack of cell surface class I expression. However, data have recently been presented demonstrating that at least one mouse class I heavy chain can be expressed on the cell surface in the absence of beta 2m. These results raised the questions of whether the lack of beta 2m is the only defect in Daudi and whether transfer of this single gene could restore surface class I expression. We found that transfection of the mouse beta 2m gene into Daudi indeed rescued cell surface expression of class I HLA molecules, and that these molecules could be recognized both by monomorphic and allospecific mAbs. CTL clones specific for HLA-B17 or a determinant shared by HLA-B17 and HLA-A2 killed the Daudi cells transfected with the beta 2m gene, but not untransfected Daudi or Daudi transfected with vector alone. Mouse beta 2m on the transfected Daudi cells could exchange with human beta 2m when the cells were incubated in human serum. This exchange did not alter the ability of the cells to be killed by the specific CTLs. These results demonstrate that the lack of beta 2m is the sole reason for lack of surface class I molecules in Daudi cells, and that beta 2m is required for cell surface expression of the specific class I heavy chains of Daudi.

    View details for Web of Science ID A1988M473200004

    View details for PubMedID 3279151

  • L3T4 AND THE IMMUNOGLOBULIN GENE SUPERFAMILY - NEW RELATIONSHIPS BETWEEN THE IMMUNE-SYSTEM AND THE NERVOUS-SYSTEM IMMUNOLOGICAL REVIEWS Parnes, J. R., Hunkapiller, T. 1987; 100: 109-127

    Abstract

    L3T4 is a mouse cell surface protein expressed on most thymocytes and on the subset of mature T cells that recognizes class II MHC molecules. Its primary function on T cells is most likely that of increasing the avidity of the interaction between T cells and antigen-presenting or target cells. It may accomplish this by binding to a nonpolymorphic region on class II MHC molecules. The cDNA and gene encoding L3T4 have been isolated and sequenced. Analysis of the amino acid sequence predicted by the nucleotide sequence indicates that L3T4 is a member of the Ig gene superfamily. It is most closely related to Ig and Tcr V regions. Although the amino-terminal domain of L3T4 is the portion of the molecule that is most similar to V-regions, L3T4 is one of the polydomain members of the Ig gene superfamily. Studies of the expression of L3T4 mRNA in various tissues led to the surprising finding that this gene is transcribed not only in T lymphoid cells, but also in brain. The predominant form of L3T4 mRNA expressed in brain is foreshortened as compared to that in T lineage cells, and it is most likely the product of a distinct transcriptional start site. If translated, the protein encoded by this brain transcript would be 217 amino acids in length and would lack the signal peptide and the amino-terminal 214 amino acids of the mature protein. It is not known whether a stable protein product is synthesized from this mRNA or what its function might be. However, these findings place L3T4 in an intriguing class of Ig gene superfamily members characterized by coexpression in the immune system and the nervous system.

    View details for Web of Science ID A1987L471200006

    View details for PubMedID 3326818

  • STRUCTURE OF THE MOUSE GENE ENCODING CD4 AND AN UNUSUAL TRANSCRIPT IN BRAIN PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA GORMAN, S. D., Tourvieille, B., Parnes, J. R. 1987; 84 (21): 7644-7648

    Abstract

    The T-cell differentiation antigen CD4 plays an important role in the function of T cells that recognize class II major histocompatibility complex proteins. Mouse CD4 (L3T4) has previously been shown to be evolutionarily related to immunoglobulin variable regions based on the predicted protein sequence from cDNA clones. The gene encoding L3T4 was found to be transcribed not only in a subset of T-lineage cells but also unexpectedly in brain, where a shorter transcript was found. In the present study the gene encoding L3T4 is shown to span 26 kilobases and to contain 10 exons. The structural organization is similar to that of other members of the immunoglobulin gene superfamily except for the striking presence of an intron in the middle of the sequence encoding the amino-terminal immunoglobulin-like homology unit. The structure of the shorter L3T4 transcript in mouse brain has been determined. This mRNA appears to be generated from a transcriptional start site within the coding sequence in exon VI. If translated, this transcript would encode a protein of 217 amino acids that lacks the usual L3T4 signal peptide and the amino-terminal 214 amino acids of the mature protein.

    View details for Web of Science ID A1987K780500062

    View details for PubMedID 2823269

Conference Proceedings


  • ALTERATION OF T-CELL LINEAGE COMMITMENT BY EXPRESSION OF A HYBRID CD8/CD4 TRANSGENE Seong, R. H., Parnes, J. R. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1992: 79-87

    View details for Web of Science ID A1992BX11S00011

    View details for PubMedID 1485567

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