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Current Research and Scholarly Interests


One of our main research focuses is to define γδ T cell function so that we can better understand host immune defense. γδ T cells, together with B cells and αβ T cells, are the only cells that use somatic V, D, J gene rearrangement to generate diverse antigen receptors. All three types of cells are present together in all but the most primitive vertebrates, suggesting that each population contributes to host immune competence uniquely and that all three are necessary for maintaining immune competence. Functional analysis indicates that in infections, γδ T cells respond earlier than αβ T cells do; and also emerge late after pathogen numbers start to decline. Thus, these cells may be involved in both establishing and resolving the inflammatory response. Our past studies indicate that γδ T cells and αβ T cells are clearly distinct in their antigen recognition and activation requirements and also in antigen-specific repertoire and effector-function development. These aspects allow γδ T cells to occupy unique temporal and functional niches in host immune defense. We are following up on these studies to determine how γδ T cell function affect the development and the termination of the inflammatory response and to study γδ T cells function in infections and autoimmune diseases. These include a mouse model of Toxoplasma gondii infection (in collaboration with Dr. John Boothryod) and celiac patients in response to gluten challenge (in collaboration with Dr. Mark Davis). We will expand the analysis to TB patients.

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • The natural and the inducible: interleukin (IL)-17-producing ?d T cells. Trends in immunology Chien, Y., Zeng, X., Prinz, I. 2013; 34 (4): 151-154

    Abstract

    ?? T cells are the major initial interleukin (IL)-17 producers in acute infections. Recent studies have indicated that some ?? T cells have IL-17-producing capabilities without explicit induction of an immune response. They are preferentially localized in barrier tissues and are likely to originate from fetal ?? thymocytes. In addition, ?? T cells present in the secondary lymphoid organs will mature and differentiate to produce IL-17 after antigen encounter in an immune response. Based on these studies, we propose that there are two different sets of IL-17-producing ?? T cells (T??17) referred to as the 'natural' and the 'inducible' T??17 cells. This review focuses on recent publications leading to the delineation of these two types of cells and their implied roles in host immune defense.

    View details for DOI 10.1016/j.it.2012.11.004

    View details for PubMedID 23266231

  • Correlation of gene expression and genome mutation in single B-cells. PloS one Weinstein, J. A., Zeng, X., Chien, Y. H., Quake, S. R. 2013; 8 (6): e67624

    Abstract

    High-throughput measurement of gene-expression and immune receptor repertoires have recently become powerful tools in the study of adaptive immune response. However, despite their now-widespread use, both tend to discard cell identity by treating cell populations in bulk, and therefore lose the correlation between genetic variability and gene-expression at the single cell level. In order to recover this information, we developed a method to simultaneously measure gene expression profiles and genome mutations in single cells. We applied this method by quantifying the relationships between gene expression and antibody mutation in ensembles of individual B-cells from immunized mice. The results reveal correlations reflecting the manner in which information propagates between a B-cell's antigen receptors, its gene expression, and its mutagenic machinery, and demonstrate the power of this approach to illuminate both heterogeneity and physiology in cell populations.

    View details for PubMedID 23840752

  • gamma delta T Cells Recognize a Microbial Encoded B Cell Antigen to Initiate a Rapid Antigen-Specific Interleukin-17 Response IMMUNITY Zeng, X., Wei, Y., Huang, J., Newell, E. W., Yu, H., Kidd, B. A., Kuhns, M. S., Waters, R. W., Davis, M. M., Weaver, C. T., Chien, Y. 2012; 37 (3): 524-534

    Abstract

    ?? T cells contribute uniquely to immune competence. Nevertheless, how they function remains an enigma. It is unclear what most ?? T cells recognize, what is required for them to mount an immune response, and how the ?? T cell response is integrated into host immune defense. Here, we report that a noted B cell antigen, the algae protein phycoerythrin (PE), is a murine and human ?? T cell antigen. Employing this specificity, we demonstrated that antigen recognition activated naive ?? T cells to make interleukin-17 and respond to cytokine signals that perpetuate the response. High frequencies of antigen-specific ?? T cells in naive animals and their ability to mount effector response without extensive clonal expansion allow ?? T cells to initiate a swift, substantial response. These results underscore the adaptability of lymphocyte antigen receptors and suggest an antigen-driven rapid response in protective immunity prior to the maturation of classical adaptive immunity.

    View details for DOI 10.1016/j.immuni.2012.06.011

    View details for Web of Science ID 000309199000016

    View details for PubMedID 22960222

  • Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation CELL HOST & MICROBE Jensen, K. D., Wang, Y., Wojno, E. D., Shastri, A. J., Hu, K., Cornel, L., Boedec, E., Ong, Y., Chien, Y., Hunter, C. A., Boothroyd, J. C., Saeij, J. P. 2011; 9 (6): 472-483

    Abstract

    European and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, type II, and type III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-?B, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection.

    View details for DOI 10.1016/j.chom.2011.04.015

    View details for Web of Science ID 000293157200006

    View details for PubMedID 21669396

  • Ligand recognition during thymic development and gamma delta T cell function specification SEMINARS IN IMMUNOLOGY Meyer, C., Zeng, X., Chien, Y. 2010; 22 (4): 207-213

    Abstract

    gammadelta T cells develop in the thymus before entering the periphery. Recent work suggests that thymic development does little to constrain gammadelta T cell antigen specificities, but instead determines their effector fate. When triggered through the T cell receptor, ligand-naïve gammadelta T cells produce IL-17, ligand-experienced cells make IFN-gamma and those that are strongly self-reactive make IL-4. Importantly, gammadelta T cells are able to make cytokines immediately upon TCR engagement. These characteristics allow gammadelta T cells to initiate an acute inflammatory response to pathogens and to host antigens revealed by injury. These advances warrant a fresh look at how gammadelta T cells may function in the immune system.

    View details for DOI 10.1016/j.smim.2010.04.002

    View details for Web of Science ID 000280383400004

    View details for PubMedID 20430644

  • Evidence for a functional sidedness to the alpha beta TCR PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kuhns, M. S., Girvin, A. T., Klein, L. O., Chen, R., Jensen, K. D., Newell, E. W., Huppa, J. B., Lillemeier, B. F., Huse, M., Chien, Y., Garcia, K. C., Davis, M. M. 2010; 107 (11): 5094-5099

    Abstract

    The T cell receptor (TCR) and associated CD3gammaepsilon, deltaepsilon, and zetazeta signaling dimers allow T cells to discriminate between different antigens and respond accordingly, but our knowledge of how these parts fit and work together is incomplete. In this study, we provide additional evidence that the CD3 heterodimers congregate on one side of the TCR in both the alphabeta and gammadeltaTCR-CD3 complexes. We also report that the other side of the alphabetaTCR mediates homotypic alphabetaTCR interactions and signaling. Specifically, an erythropoietin receptor-based dimerization assay was used to show that, upon complex assembly, the CD3epsilon chains of two CD3 heterodimers are arranged side-by-side in both the alphabeta and gammadeltaTCR-CD3 complexes. This system was also used to show that alphabetaTCRs can dimerize in the cell membrane and that mutating the unusual outer strands of the Calpha domain impairs this dimerization. Finally, we present data showing that, for CD4 T cells, the mutations that impair alphabetaTCR dimerization also alter ligand-induced calcium mobilization, TCR accumulation at the site of pMHC contact, and polarization toward the site of antigen contact. These data reveal a "functional-sidedness" to the alphabetaTCR constant region, with dimerization occurring on the side of the TCR opposite from where the CD3 heterodimers are located.

    View details for DOI 10.1073/pnas.1000925107

    View details for Web of Science ID 000275714300054

    View details for PubMedID 20202921

  • The Salmonella SPI2 Effector SseI Mediates Long-Term Systemic Infection by Modulating Host Cell Migration PLOS PATHOGENS McLaughlin, L. M., Govoni, G. R., Gerke, C., Gopinath, S., Peng, K., Laidlaw, G., Chien, Y., Jeong, H., Li, Z., Brown, M. D., Sacks, D. B., Monack, D. 2009; 5 (11)

    Abstract

    Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice. SseI inhibits normal cell migration of primary macrophages and dendritic cells (DC) in vitro, and such inhibition requires the host factor IQ motif containing GTPase activating protein 1 (IQGAP1), an important regulator of cell migration. SseI binds directly to IQGAP1 and co-localizes with this factor at the cell periphery. The C-terminal domain of SseI is similar to PMT/ToxA, a bacterial toxin that contains a cysteine residue (C1165) that is critical for activity. Mutation of the corresponding residue in SseI (C178A) eliminates SseI function in vitro and in vivo, but not binding to IQGAP1. In addition, infection with wild-type (WT) S. typhimurium suppressed DC migration to the spleen in vivo in an SseI-dependent manner. Correspondingly, examination of spleens from mice infected with WT S. typhimurium revealed fewer DC and CD4(+) T lymphocytes compared to mice infected with Delta sseI S. typhimurium. Taken together, our results demonstrate that SseI inhibits normal host cell migration, which ultimately counteracts the ability of the host to clear systemic bacteria.

    View details for DOI 10.1371/journal.ppat.1000671

    View details for Web of Science ID 000274226600025

    View details for PubMedID 19956712

  • Cutting Edge: gamma delta Intraepithelial Lymphocytes of the Small Intestine Are Not Biased toward Thymic Antigens JOURNAL OF IMMUNOLOGY Jensen, K. D., Shin, S., Chien, Y. 2009; 182 (12): 7348-7351

    Abstract

    gammadelta Tau cells, together with alphabeta Tau cells, are abundantly present in the epithelial layer of the small intestine (IEL) and are essential for the host's first line of defense. Whether or not gammadelta IELs, like alphabeta IELs, are derived from thymocytes that encounter self-Ags in the thymus is unclear. In this study, we report that a natural population of gammadelta T cells that are specific for the nonclassical MHC class I molecules T10 and T22 are present in the IEL compartment of mice that do not express T10/T22. Furthermore, the small intestinal homing receptor CCR9 is preferentially expressed on gammadelta thymocytes that have yet to encounter a ligand, and gammadelta thymocytes with high affinity for self-ligand are CCR9(low). These observations suggest that the Ag-specific repertoire of gammadelta IELs is not biased toward thymic Ags. Instead, gammadelta IELs appear suited to respond to novel Ags revealed in pathological settings.

    View details for DOI 10.4049/jimmunol.0900465

    View details for Web of Science ID 000266833900003

    View details for PubMedID 19494256

  • Thymic maturation determines gamma delta T cell function, but not their antigen specificities CURRENT OPINION IN IMMUNOLOGY Jensen, K. D., Chien, Y. 2009; 21 (2): 140-145

    Abstract

    gammadelta T cells contribute uniquely to host immune defense, but how they do so remains unclear. Recent work suggests that thymic selection does little to constrain gammadelta T cell antigen specificities, but instead determines their effector fate. When triggered through the T cell receptor, ligand-experienced cells make IFNgamma, whereas ligand-naïve gammadelta T cells produce IL-17, a major initiator of inflammation. These advances warrant a fresh look at how gammadelta T cells may function in the immune system.

    View details for DOI 10.1016/j.coi.2009.02.008

    View details for Web of Science ID 000266223400005

    View details for PubMedID 19321327

  • Thymic selection determines gamma delta T cell effector fate: Antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma IMMUNITY Jensen, K. D., Su, X., Shin, S., Li, L., Youssef, S., Yarnasaki, S., Steinman, L., Saito, T., Locksley, R. M., Davis, M. M., Baumgarth, N., Chien, Y. 2008; 29 (1): 90-100

    Abstract

    gammadelta T cells uniquely contribute to host immune defense, but how this is accomplished remains unclear. Here, we analyzed the nonclassical major histocompatibility complex class I T10 and T22-specific gammadelta T cells in mice and found that encountering antigen in the thymus was neither required nor inhibitory for their development. But when triggered through the T cell receptor, ligand-naive lymphoid-gammadelta T cells produced IL-17, whereas ligand-experienced cells made IFN-gamma. Immediately after immunization, a large fraction of IL-17(+) gammadelta T cells were found in the draining lymph nodes days before the appearance of antigen-specific IL-17(+) *beta T cells. Thus, thymic selection determines the effector fate of gammadelta T cells rather than constrains their antigen specificities. The swift IL-17 response mounted by antigen-naive gammadelta T cells suggests a critical role for these cells at the onset of an acute inflammatory response to novel antigens.

    View details for DOI 10.1016/j.immuni.2008.04.022

    View details for Web of Science ID 000257905400013

    View details for PubMedID 18585064

  • An autonomous CDR3 delta is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by gamma delta T cells NATURE IMMUNOLOGY Adams, E. J., Strop, P., Shin, S., Chien, Y., Garcia, K. C. 2008; 9 (7): 777-784

    Abstract

    It remains unclear whether gammadelta T cell antigen receptors (TCRs) detect antigens in a way similar to antibodies or alphabeta TCRs. Here we show that reactivity between the G8 and KN6 gammadelta TCRs and the major histocompatibility complex class Ib molecule T22 could be recapitulated, with retention of wild-type ligand affinity, in an alphabeta TCR after grafting of a G8 or KN6 complementarity-determining region 3-delta (CDR3delta) loop in place of the CDR3alpha loop of an alphabeta TCR. We also found that a shared sequence motif in CDR3delta loops of all T22-reactive gammadelta TCRs bound T22 in energetically distinct ways, and that T10(d), which bound G8 with weak affinity, was converted into a high-affinity ligand by a single point mutation. Our results demonstrate unprecedented autonomy of a single CDR3 loop in antigen recognition.

    View details for DOI 10.1038/ni.1620

    View details for Web of Science ID 000256904900016

    View details for PubMedID 18516039

  • Antigen recognition by gamma delta T cells IMMUNOLOGICAL REVIEWS Chien, Y., Konigshofer, Y. 2007; 215: 46-58

    Abstract

    gammadelta T cells contribute to host immune competence uniquely. This is most likely because they have distinctive antigen-recognition properties. While the basic organization of gammadelta T-cell receptor (TCR) loci is similar to that of alphabeta TCR loci, there is a striking difference in how the diversity of gammadelta TCRs is generated. gammadelta and alphabeta T cells have different antigen-recognition requirements and almost certainly recognize a different set of antigens. While it is unclear what most gammadelta T cells recognize, the non-classical major histocompatibility complex class I molecules T10 and T22 were found to be the natural ligands for a sizable population (0.2-2%) of murine gammadelta T cells. The recognition of T10/T22 may be a way by which gammadelta T cells regulate cells of the immune system, and this system has been used to determine the antigen-recognition determinants of gammadelta T cells. T10/T22-specific gammadelta T cells have TCRs that are diverse in both V gene usage and CDR3 sequences. Their Vgamma usage reflects their tissue origin, and their antigen specificity is conferred by a motif in the TCR delta chain that is encoded by V and D segments and by P-nucleotide addition. Sequence variations around this motif modulate affinities between TCRs and T10/T22. That this CDR3 motif is important in antigen recognition is confirmed by the crystal structure of a gammadelta TCR bound to its ligand. The significance of these observations is discussed in the context of gammadelta T-cell biology.

    View details for Web of Science ID 000243973600005

    View details for PubMedID 17291278

  • gamma delta T cells - innate immune lymphocytes? CURRENT OPINION IN IMMUNOLOGY Konigshofer, Y., Chien, Y. 2006; 18 (5): 527-533

    Abstract

    It is unclear what the antigen recognition determinants of gammadelta T-cell receptors (TCRs) are. Compared with immunoglobulin and alphabeta TCRs, gammadelta TCRs have the highest potential CDR3 diversity generated by VDJ recombination. However, gammadelta T-cell reactivities seem to segregate with V gene usage, which has been taken to suggest that rearrangement has little role in generating different antigen specificities. During the past year, the CDR3 regions were found to determine the antigen specificities of T10- and T22-reactive gammadelta TCRs, a surface protein complex was identified as a ligand for human phosphoantigen-reactive gammadelta T cells, and the first co-crystal structure of a gammadelta TCR bound to its ligand was reported. These advances warrant a fresh look at gammadelta T-cell antigen recognition.

    View details for DOI 10.1016/j.coi.2006.07.008

    View details for Web of Science ID 000240816300003

    View details for PubMedID 16879956

  • Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chaparro, R. J., Konigshofer, Y., Beilhack, G. F., Shizuru, J. A., McDevitt, H. O., Chien, Y. 2006; 103 (33): 12475-12480

    Abstract

    Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant C57BL/6/scid mice. Our results suggest that the NOD genetic background may predispose them to diabetic complications, including insulin resistance in the absence of high circulating glucose levels and without autoimmune destruction of their beta cells. Several of these genes lie within known type 1 and 2 diabetes loci. These data suggest that the NOD mouse may be a good candidate to study an interface between type 1 and type 2 diabetes.

    View details for DOI 10.1073/pnas.0604317103

    View details for Web of Science ID 000239867500050

    View details for PubMedID 16895987

  • Structure of a gamma delta T cell receptor in complex with the nonclassical MHC T22 SCIENCE Adams, E. J., Chien, Y. H., Garcia, K. C. 2005; 308 (5719): 227-231

    Abstract

    Gammadelta T cell receptors (TCRs), alphabeta TCRs, and antibodies are the three lineages of somatically recombined antigen receptors. The structural basis for ligand recognition is well defined for alphabeta TCR and antibodies but is lacking for gammadelta TCRs. We present the 3.4 A structure of the murine gammadelta TCR G8 bound to its major histocompatibility complex (MHC) class Ib ligand, T22. G8 predominantly uses germline-encoded residues of its delta chain complementarity-determining region 3 (CDR3) loop to bind T22 in an orientation substantially different from that seen in alphabeta TCR/peptide-MHC. That junctionally encoded G8 residues play an ancillary role in binding suggests a fusion of innate and adaptive recognition strategies.

    View details for DOI 10.1126/science.1106885

    View details for Web of Science ID 000228273700045

    View details for PubMedID 15821084

  • Antigen recognition determinants of gamma delta T cell receptors SCIENCE Shin, S., El-Diwany, R., Schaffert, S., Adams, E. J., Garcia, K. C., Pereira, P., Chien, Y. H. 2005; 308 (5719): 252-255

    Abstract

    The molecular basis of gammadelta T cell receptor (TCR) recognition is poorly understood. Here, we analyze the TCR sequences of a natural gammadelta T cell population specific for the major histocompatibility complex class Ib molecule T22. We find that T22 recognition correlates strongly with a somatically recombined TCRdelta complementarity-determining region 3 (CDR3) motif derived from germ line-encoded residues. Sequence diversity around these residues modulates TCR ligand-binding affinities, whereas V gene usage correlates mainly with tissue origin. These results show how an antigen-specific gammadelta TCR repertoire can be generated at a high frequency and suggest that gammadelta T cells recognize a limited number of antigens.

    View details for DOI 10.1126/science.1106480

    View details for Web of Science ID 000228273700053

    View details for PubMedID 15821090

  • The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation JOURNAL OF EXPERIMENTAL MEDICINE Gerke, C., FALKOW, S., Chien, Y. H. 2005; 201 (3): 361-371

    Abstract

    T cell responses are critical to the survival of Yersinia-infected animals. Yersinia have the ability to directly suppress T lymphocyte activation through the virulence factor YopH, a tyrosine phosphatase. Using single cell video microscopy and FACS analysis, here we show that even an average of one Yersinia per T cell is sufficient to inhibit or alter T cell responses. This efficient inhibition is traced to specific targeting by YopH of the adaptor proteins, linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kD (SLP-76), which are crucial for T cell antigen receptor (TCR) signaling. A catalytically inactive YopH translocated via the type III secretory pathway from the bacteria into T cells primarily binds to LAT and SLP-76. Furthermore, among the proteins of the TCR signaling pathway, the tyrosine phosphorylation levels of LAT and SLP-76 are the most affected in T cells exposed to low numbers of Yersinia pseudotuberculosis. This is the first example showing that a pathogen targets these adaptor proteins in the TCR signaling pathway, suggesting a novel mechanism by which pathogens may efficiently alter T cell-mediated immune responses.

    View details for DOI 10.1084/jem.20041120

    View details for Web of Science ID 000227092900007

    View details for PubMedID 15699071

  • Attributes of gamma delta intraepithelial lymphocytes as suggested by their transcriptional profile PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fahrer, A. M., Konigshofer, Y., Kerr, E. M., Ghandour, G., Mack, D. H., DAVIS, M. M., Chien, Y. H. 2001; 98 (18): 10261-10266

    Abstract

    gammadelta T lymphocytes in the intestinal intraepithelial layer (gammadelta IELs) are thought to contribute to immune competence, but their actual function remains poorly understood. Here we used DNA microarrays to study the gene expression profile of gammadelta IELs in a Yersinia infection system to better define their roles. To validate this approach, mesenteric lymph node CD8(+) alphabeta T cells were similarly analyzed. The transcription profiles show that, whereas lymph node CD8(+) alphabeta T cells must be activated to become cytotoxic effectors, gammadelta IELs are constitutively activated and appear to use different signaling cascades. Our data suggest that gammadelta IELs may respond efficiently to a broad range of pathological situations irrespective of their diverse T cell antigen receptor repertoire. gammadelta IELs may modulate local immune responses and participate in intestinal lipid metabolism, cholesterol homeostasis, and physiology. This study provides a strong basis for further investigations of the roles of these cells as well as mucosal immune defense in general.

    View details for Web of Science ID 000170738000045

    View details for PubMedID 11526237

  • Antigen-recognition properties of murine gamma delta T cells SPRINGER SEMINARS IN IMMUNOPATHOLOGY Chien, Y. H., Hampl, J. 2000; 22 (3): 239-250

    View details for Web of Science ID 000165436700005

    View details for PubMedID 11116955

  • A population of murine gamma delta T cells that recognize an inducible MHC class lb molecule SCIENCE Crowley, M. P., Fahrer, A. M., Baumgarth, N., Hampl, J., Gutgemann, I., Teyton, L., Chien, Y. H. 2000; 287 (5451): 314-316

    Abstract

    Although gammadelta T cells are implicated in regulating immune responses, gammadelta T cell-ligand pairs that could mediate such regulatory functions have not been identified. Here, the expression of the major histocompatibility complex (MHC) class Ib T22 and the closely related T10 molecules is shown to be activation-induced, and they confer specificity to about 0.4% of the gammadelta T cells in normal mice. Thus, the increased expression of T22 and/or T10 might trigger immunoregulatory gammadelta T cells during immune responses. Furthermore, the fast on-rates and slow off-rates that characterize this receptor/ligand interaction would compensate for the low ligand stability and suggest a high threshold for gammadelta T cell activation.

    View details for Web of Science ID 000084769600043

    View details for PubMedID 10634788

  • Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, YopH JOURNAL OF EXPERIMENTAL MEDICINE Yao, T., Mecsas, J., Healy, J. I., FALKOW, S., Chien, Y. H. 1999; 190 (9): 1343-1350

    Abstract

    The acquired immune responses are crucial to the survival of Yersinia-infected animals. Mice lacking T cells are sensitive to Yersinia infection, and a humoral response to Yersinia can be protective. Diverse mechanisms for Yersinia to impair and evade the host innate immune defense have been suggested, but the effects of Yersinia on lymphocytes are not known. Here, we demonstrate that after a transient exposure to Y. pseudotuberculosis, T and B cells are impaired in their ability to be activated through their antigen receptors. T cells are inhibited in their ability to produce cytokines, and B cells are unable to upregulate surface expression of the costimulatory molecule, B7.2, in response to antigenic stimulation. The block of lymphocyte activation results from the inhibition of early phosphorylation events of the antigen receptor signaling complex. Through the use of Y. pseudotuberculosis mutants, we show that the inhibitory effect in both T cells and B cells is dependent on the production of Yersinia outermembrane protein (Yop) H, a tyrosine phosphatase. Our results suggest a mechanism by which the pathogenic bacteria may modulate a wide range of T and B cell-mediated immune responses.

    View details for Web of Science ID 000083552800014

    View details for PubMedID 10544205

  • The specificity of a weak gamma delta TCR interaction can be modulated by the glycosylation of the ligand JOURNAL OF IMMUNOLOGY Hampl, J., SCHILD, H., Litzenberger, C., Baron, M., Crowley, M. P., Chien, Y. H. 1999; 163 (1): 288-294

    Abstract

    The gamma delta T cell clone LBK5 recognizes the MHC molecule IEk. Here, we demonstrate that the affinity of this interaction is weaker than those typically reported for alpha beta TCRs that recognize peptide/MHC complexes. Consistent with our previous finding that peptide bound to the IE molecule does not confer specificity, we show that the entire epitope for LBK5 is contained within the polypeptide chains of the molecule, centered around the polymorphic residues 67 and 70 of the IE beta-chain. However, LBK5 recognition is profoundly influenced by the N-linked glycosylation at residue 82 of the IE alpha-chain. Since infected, stressed, or transformed cells often change the posttranslational modifications of their surface glycoproteins, this finding suggests a new way in which gamma delta T cell Ag recognition can be regulated.

    View details for Web of Science ID 000080973700038

    View details for PubMedID 10384127

  • Visualizing lymphocyte recognition IMMUNOLOGY AND CELL BIOLOGY Wulfing, C., Chien, Y. H., DAVIS, M. M. 1999; 77 (2): 186-187

    Abstract

    Studies of T cell recognition have entered new territory now that some of the basic issues of genetics, biochemistry and structure have been addressed, at least in outline form. In the present work, the focus is on a new aspect of T cell recognition that goes beyond classical biochemistry to ask, how to TCR and other cell surface molecules cooperate to initiate and control recognition?'

    View details for Web of Science ID 000079676100012

    View details for PubMedID 10234556

  • Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development JOURNAL OF EXPERIMENTAL MEDICINE Messika, E. J., Lu, P. S., Sung, Y. J., Yao, T., Chi, J. T., Chien, Y. H., DAVIS, M. M. 1998; 188 (3): 515-525

    Abstract

    The B lymphocyte-induced maturation protein (Blimp-1) upregulates the expression of syndecan-1 and J chain and represses that of c-myc. We have transfected Blimp-1 into two sublines of the BCL1 B cell lymphoma that represent distinct stages of B cell development in secondary lymphoid tissues. After interleukin (IL)-2 and IL-5 stimulation, the BCL1 3B3 cells differentiate into centrocyte-like cells, whereas the BCL1 5B1b cells blast and appear to be blocked at the centroblast stage. This blasting effect and the increase in IgM secretion that follows it can be blocked by a dominant negative form of Blimp-1. At the same time, the ectopic expression of Blimp-1 in these partially activated cells induces an apoptotic response that also can be suppressed by the same dominant negative protein. A similar effect was noticed when Blimp-1 was expressed in the mature L10A and the immature WEHI-231 lines, indicating this may be a general effect at earlier stages of the B cell development, and distinct from the ability of Blimp-1 to induce maturation in late stages of differentiation. Truncation mutants indicate that the induction of the apoptotic response relies mainly on 69 amino acids within Blimp-1's proline-rich domain. We propose that Blimp-1 expression defines a checkpoint beyond which fully activated B cells proceed to the plasma cell stage, whereas immature and partially activated cells are eliminated at this point.

    View details for Web of Science ID 000075300300010

    View details for PubMedID 9687529

  • Induction of rapid T cell activation and tolerance by systemic presentation of an orally administered antigen IMMUNITY Gutgemann, I., Fahrer, A. M., Altman, J. D., DAVIS, M. M., Chien, Y. H. 1998; 8 (6): 667-673

    Abstract

    To understand how orally introduced antigen regulates peripheral immune responses, we fed cytochrome c protein to mice transgenic for the beta chain of a cytochrome c-specific TCR and followed the antigen-specific T cell responses with a cyt c/I-Ek tetramer staining reagent. We find that within 6 hr of cytochrome c administration, antigen-specific systemic T cell activation is induced, and spleen cells gain the ability to stimulate cytochrome c-specific T cell responses. Feeding multiple low doses of cytochrome c down-regulates the systemic immune response, which can be correlated with a reduction of antigen-specific T cells and not with immune deviation. These results suggest that systemic distribution of antigen contributes significantly to oral tolerance induction.

    View details for Web of Science ID 000074396300002

    View details for PubMedID 9655480

  • Ligand recognition by alpha beta T cell receptors ANNUAL REVIEW OF IMMUNOLOGY Davis, M. M., BONIFACE, J. J., Reich, Z., Lyons, D., Hampl, J., Arden, B., Chien, Y. H. 1998; 16: 523-?

    Abstract

    While still incomplete, the first data concerning the biochemistry of T cell receptor-ligand interactions in cell-free systems seem to have considerable predictive value regarding whether a T cell response is strong or weak or suppressive. This data will help considerably in elucidating the mechanisms behind T cell responsiveness. Also of great interest are the first structures of T cell receptor molecules and, particularly, TCR-ligand complexes. These appear to confirm earlier suggestions of a fixed orientation for TCR engagement with peptide/MHC and should form the basis for understanding higher oligomers, evidence for which has also just emerged. We conclude with an analysis of the highly diverse CDR3 loops found in all antigen receptor molecules and suggest that such regions form the core of both TCR and antibody specificity.

    View details for Web of Science ID 000073129400019

    View details for PubMedID 9597140

  • CD4 augments the response of a T cell to agonist but not to antagonist ligands IMMUNITY Hampl, J., Chien, Y. H., DAVIS, M. M. 1997; 7 (3): 379-385

    Abstract

    The recognition of peptide variants by the T cell receptor (TCR) has revealed a wide range of possible responses. Here, using a series of CD4+ and CD4- variants of the same T cell hybridoma, we find that while the expression of CD4 converts weak agonists into full agonists, none of the antagonist peptides are efficiently recognized as agonists. Furthermore, in antagonist assays, little difference can be seen in the response of CD4+ and CD4- T cells. Together with previous work showing a marked difference in stability between TCR binding to agonist versus antagonist ligands, these data suggest that CD4 engagement occurs after a TCR-peptide/MHC complex has formed and that it requires a certain minimal half-life of the ternary complex to be fully engaged in signaling.

    View details for Web of Science ID A1997XY83000007

    View details for PubMedID 9324358

  • The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the gamma delta T cell, G8 JOURNAL OF EXPERIMENTAL MEDICINE Crowley, M. P., Reich, Z., Mavaddat, N., Altman, J. D., Chien, Y. H. 1997; 185 (7): 1223-1230

    Abstract

    Recent studies have shown that many nonclassical major histocompatibility complex (MHC) (class 1b) molecules have distinct antigen-binding capabilities, including the binding of nonpeptide moieties and the binding of peptides that are different from those bound to classical MHC molecules. Here, we show that one of the H-2T region-encoded molecules, T10, when produced in Escherichia coli, can be folded in vitro with beta2-microglobulin (beta2m) to form a stable heterodimer in the absence of peptide or nonpeptide moieties. This heterodimer can be recognized by specific antibodies and is stimulatory to the gammadelta T cell clone, G8. Circular dichroism analysis indicates that T10/beta2m has structural features distinct from those of classical MHC class I molecules. These results suggest a new way for MHC-like molecules to adopt a peptide-free structure and to function in the immune system.

    View details for Web of Science ID A1997WU18300008

    View details for PubMedID 9104809

  • T cell receptor biochemistry, repertoire selection and general features of TCR and Ig structure MOLECULAR BASIS OF CELLULAR DEFENCE MECHANISMS DAVIS, M. M., Lyons, D. S., Altman, J. D., MCHEYZERWILLIAMS, M., Hampl, J., BONIFACE, J. J., Chien, Y., Nossal, Zinkernagel, Miller, Paul, Kirberg, MELCHERS, Mosmann, Goodnow 1997; 204: 94-104

    Abstract

    T cell recognition is a central event in the development of most immune responses, whether appropriate or inappropriate (i.e. autoimmune). We are interested in reducing T cell recognition to its most elemental components and relating this to biological outcome. In a model system involving a cytochrome c-specific I-Ek restricted T cell receptor (TCR) derived from the 2B4 hybridoma, we have studied the interaction of soluble TCR and soluble peptide-MHC complexes using surface plasmon resonance. We find a striking continuum in which biological activity correlates best with the dissociation rate of the TCR from the peptide-MHC complex. In particular, we have found that weak agonists have significantly faster off-rates than strong agonists and that antagonists have even faster off-rates. This suggests that the stability of TCR binding to a given ligand is critically important with respect to whether the T cell is stimulated, inhibited or remains indifferent. It also suggests that the phenomenon of peptide antagonists might be explained purely by kinetic models and that conformation, either inter- or intramolecular, may not be a factor. We have also studied TCR repertoire selection during the establishment of a cytochrome c response, initially using an anti-TCR antibody strategy, but more recently using peptide-MHC tetramers as antigen-specific staining reagents. These tetramers work well with either class I or class II MHC-specific TCRs and have many possible applications. Lastly, we have also tried to correlate the structural and genetic features of TCRs with their function. Recent data on TCR structure as well as previous findings with antibodies suggest that both molecules are highly dependent on CDR3 length and sequence variation to form specific contacts with antigens. This suggests a general "logic' behind TCR and Ig genetics as it relates to structure and function that helps to explain certain anomalous findings and makes a number of clear predictions.

    View details for Web of Science ID A1997BH80V00009

    View details for PubMedID 9107414

  • Early biochemical signals arise from low affinity TCR-ligand reactions at the cell-cell interface JOURNAL OF EXPERIMENTAL MEDICINE Beeson, C., Rabinowitz, J., Tate, K., Gutgemann, I., Chien, Y. H., Jones, P. P., DAVIS, M. M., McConnell, H. M. 1996; 184 (2): 777-782

    Abstract

    The kinetics of acid release by a mixture of T cells and antigen presenting cells were measured with a microphysiometer during a brief exposure to antigenic peptides. We find that some of the early biochemical events that lead to cellular proliferation cause a specific increase in the rate of acid release. The duration of this increase in acid release reflects the life-time of the peptide-MHC complexes. Peptides that form long-lived complexes produce a response that is stable for more than an hour. Serial TCR engagement is suggested by the observation that the amplitude of this stable response can be rapidly shifted up or down with additional agonist peptide or with antibodies that block T cell receptor binding. Cells briefly exposed to a peptide that forms short-lived peptide-MHC complexes produce a response that decays rapidly as peptide is washed away. A quantitative analysis of the kinetics of this decay in acidification demonstrates that intercellular TCR-ligand reactions are rapid, reversible, and of low apparent affinity with < 20% of peptide-MHC ligand bound to a TCR at any one time. These results demonstrate that the fraction of peptide-MHC ligands bound to TCRs at the cell-cell interface is no higher than anticipated from the affinities observed in solution for isolated TCRs and ligands.

    View details for Web of Science ID A1996VC33700052

    View details for PubMedID 8760833

  • A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists IMMUNITY Lyons, D. S., Lieberman, S. A., Hampl, J., BONIFACE, J. J., Chien, Y. H., Berg, L. J., DAVIS, M. M. 1996; 5 (1): 53-61

    Abstract

    T lymphocyte activation is mediated by the interaction of specific TCR with antigenic peptides bound to MHC molecules. Single amino acid substitutions are often capable of changing the effect of a peptide from stimulatory to antagonistic. Using surface plasmon resonance, we have analyzed the interaction between a complex consisting of variants of the MCC peptide bound to a mouse class II MHC (Ek) and a specific TCR. Using both an improved direct binding method as well as a novel inhibition assay, we show that the affinities of three different antagonist peptide-Ek complexes are approximately 10-50 times lower than that of the wildtype MCC-Ek complex for the TCR, largely due to an increased off-rate. These results suggest that the biological effects of peptide antagonists and partial agonists may be largely based on kinetic parameters.

    View details for Web of Science ID A1996UZ45400006

    View details for PubMedID 8758894

  • Recognition by gamma/delta T cells ANNUAL REVIEW OF IMMUNOLOGY Chien, Y. H., Jores, R., Crowley, M. P. 1996; 14: 511-532

    Abstract

    In contrast with the study of alpha beta T cells, that of gamma delta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alpha beta T cells. During the past few years, many studies, especially with mice lacking either alpha beta or gamma delta T cells, have demonstrated that gamma delta T cells can contribute to immune competence, but they do so in a way that is distinct from alpha beta T cells. It is also evident that gamma delta T cells may not recognize antigen the same way as do alpha beta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gamma delta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gamma delta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gamma delta T cells can respond to ligands that are different from those of alpha beta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gamma delta and alpha beta T cells recognize antigens differently and suggests that gamma delta T cells may be more like immunoglobulins in their recognition properties. gamma delta T cells share many cell surface proteins with alpha beta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gamma delta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gamma delta T cells greater flexibility than the more classical type of alpha beta T cell-mediated cellular immunity.

    View details for Web of Science ID A1996UH42900021

    View details for PubMedID 8717523

  • GAMMA-DELTA T-CELLS - T-CELLS WITH B-CELL-LIKE RECOGNITION PROPERTIES CURRENT BIOLOGY Chien, Y. H., Jores, R. 1995; 5 (10): 1116-1118

    Abstract

    Recent results suggest there are fundamental differences in antigen recognition by alpha beta and gamma delta T-cell receptors, which might underlie possible differences in function between these two types of T cell.

    View details for Web of Science ID A1995TA46400011

    View details for PubMedID 8548281

  • The recognition of MHC molecules by gamma delta T cells. Behring Institute Mitteilungen SCHILD, H., Chien, Y. H. 1994: 113-123

    View details for PubMedID 7998905

  • THE NATURE OF MAJOR HISTOCOMPATIBILITY COMPLEX RECOGNITION BY GAMMA-DELTA-T-CELLS CELL SCHILD, H., Mavaddat, N., Litzenberger, C., Ehrich, E. W., DAVIS, M. M., Bluestone, J. A., Matis, L., Draper, R. K., Chien, Y. H. 1994; 76 (1): 29-37

    Abstract

    Despite intensive efforts, the general rules for gamma delta T cell recognition remain undefined. Here, we take advantage of the detailed knowledge of the molecular structure and biosynthetic pathways of major histocompatibility complex (MHC) molecules to analyze the recognition properties of the gamma delta T cell clones LBK5 (specific for the class II MHC, IEk) and G8 (specific for the nonclassical class I MHC, TL10b). We find that the activation of these clones requires neither class I nor class II antigen-processing and that peptides do not confer specificity. Epitope mapping also shows that the topology of gamma delta T cell receptor interaction with the MHC is distinct from that of alpha beta T cells. These results suggest that the molecular nature of gamma delta T cell recognition is fundamentally different than that of alpha beta T cells.

    View details for Web of Science ID A1994MR49500004

    View details for PubMedID 8287478

  • CDR3 LENGTH IN ANTIGEN-SPECIFIC IMMUNE RECEPTORS JOURNAL OF EXPERIMENTAL MEDICINE ROCK, E. P., SIBBALD, P. R., DAVIS, M. M., Chien, Y. H. 1994; 179 (1): 323-328

    Abstract

    In both immunoglobulins (Ig) and T cell receptors (TCR), the rearrangement of V, D, and J region sequence elements during lymphocyte maturation creates an enormous degree of diversity in an area referred to as the complementarity determining region 3 (CDR3) loop. Variations in the particular V, D, and J elements used, precise points of recombination, and random nucleotide addition all lead to extensive length and sequence heterogeneity. CDR3 loops are often critical for antigen binding in Igs and appear to provide the principal peptide binding residues in TCRs. To better understand the physical and selective constraints on these sequences, we have compiled information on CDR3 size variation for Ig H, L (kappa and lambda) and TCR alpha, beta, gamma, and delta. Ig H and TCR delta CDR3s are the most variable in size and are significantly longer than L and gamma chains, respectively. In contrast, TCR alpha and beta chain distributions are highly constrained, with nearly identical average CDR3 lengths, and their length distributions are not altered by thymic selection. Perhaps most significantly, these CDR3 length profiles suggest that gamma/delta TCRs are more similar to Igs than to alpha/beta TCRs in their putative ligand binding region, and thus gamma/delta and alpha/beta T cells may have fundamentally different recognition properties.

    View details for Web of Science ID A1994MP51700033

    View details for PubMedID 8270877

  • HOW ALPHA-BETA-T-CELL RECEPTORS SEE PEPTIDE MHC COMPLEXES IMMUNOLOGY TODAY Chien, Y. H., DAVIS, M. M. 1993; 14 (12): 597-602

    Abstract

    Recent results have added new information to our understanding of alpha beta T-cell receptor mediated recognition. In particular, we find that the V(D)J junction or 'CDR3' portion of TCR alpha and beta seem most important in contacting peptides bound to MHC molecules, consistent with previous predictions. Surprisingly, these same CDR3-peptide contacts also appear to have a major influence on the TCR-MHC molecule interactions as well.

    View details for Web of Science ID A1993MK79800005

    View details for PubMedID 8305132

  • T-CELL RECEPTOR INTERACTION WITH PEPTIDE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND SUPERANTIGEN MHC LIGANDS IS DOMINATED BY ANTIGEN JOURNAL OF EXPERIMENTAL MEDICINE Ehrich, E. W., DEVAUX, B., ROCK, E. P., JORGENSEN, J. L., DAVIS, M. M., Chien, Y. H. 1993; 178 (2): 713-722

    Abstract

    While recent evidence strongly suggests that the third complementarity determining regions (CDR3s) of T cell receptors (TCRs) directly contact antigenic peptides bound to major histocompatibility complex (MHC) molecules, the nature of other TCR contact(s) is less clear. Here we probe the extent to which different antigens can affect this interaction by comparing the responses of T cells bearing structurally related TCRs to cytochrome c peptides and staphylococcal enterotoxin A (SEA) presented by 13 mutant antigen-presenting cell (APC) lines. Each APC expresses a class II MHC molecule (I-Ek) with a single substitution of an amino acid residue predicted to be located on the MHC alpha helices and to point "up" towards the TCR. We find that very limited changes (even a single amino acid) in either a CDR3 loop of the TCR or in a contact residue of the antigenic peptide can have a profound effect on relatively distant TCR/MHC interactions. The extent of these effects can be as great as that observed between T cells bearing entirely different TCRs and recognizing different peptides. We also find that superantigen presentation entails a distinct mode of TCR/MHC interaction compared with peptide presentation. These data suggest that TCR/MHC contacts can be made in a variety of ways between the same TCR and MHC, with the final configuration apparently dominated by the antigen. These observations suggest a molecular basis for recent reports in which either peptide analogues or superantigens trigger distinct pathways of T cell activation.

    View details for Web of Science ID A1993LP83000037

    View details for PubMedID 8393480

  • TOPOLOGY AND AFFINITY OF T-CELL RECEPTOR MEDIATED RECOGNITION OF PEPTIDE MHC COMPLEXES CURRENT OPINION IN IMMUNOLOGY DAVIS, M. M., Chien, Y. H. 1993; 5 (1): 45-49

    Abstract

    Significant progress has been made on several long-standing issues regarding T-cell receptor mediated recognition of antigen-MHC complexes. For one, early data suggest that the affinity of the T-cell receptor for the peptide-MHC complex is extremely low, with a KD of approximately 10(-4)-10(-5)M, much weaker than most antibody-antigen interactions. The fact that this affinity is lower than that of some T-cell adhesion molecules for their ligands could have important implications for immune surveillance. A second area of interest is the topology of T-cell receptor recognition; evidence of direct contact between the third complementarity determining region of the T-cell receptor and peptide determinants has been obtained. In addition, the orientation of the T-cell receptor with respect to several antigen-MHC complexes has been predicted. They suggest that whereas most or all peptides seem to bind in the same orientation in both class I and class II MHC molecules, the orientation of the T-cell receptor over the peptide-MHC complex may not be fixed.

    View details for Web of Science ID A1993KN29300008

    View details for PubMedID 8452673

  • DEVELOPMENT OF GAMMA-DELTA T-CELL SUBSETS FROM FETAL HEMATOPOIETIC STEM-CELLS ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Ikuta, K., Kina, T., MacNeil, I., Uchida, N., Peault, B., Chien, Y. H., Weissman, I. L. 1992; 651: 21-32

    Abstract

    Hematopoietic stem cells (HSC) were isolated from mouse fetus, and their developmental potential was compared with adult HSC. Donor-derived V gamma 3+T cells were detected in fetal thymic lobes, repopulated in vitro with fetal liver HSC, but not in those with adult bone marrow HSC. Single clonogenic fetal HSC gave rise to thymic progeny that include V gamma 3+, other gamma delta+, and alpha beta+ T cells. No V gamma 3+ T cells were detected in adult thymus injected intrathymically with either fetal or adult HSC. These results support a hypothesis that only fetal HSC have the capacity to differentiate into V gamma 3+ T cells in the fetal thymic microenvironment, and that the developmental potential of HSC may change during ontogeny.

    View details for Web of Science ID A1992JM21900003

    View details for PubMedID 1599125

  • A GAMMA-DELTA T-CELL RECEPTOR HETERODIMER INDUCES THE EXPRESSION OF CD4 AND CD8 IN THYMOCYTES JOURNAL OF EXPERIMENTAL MEDICINE Iwashima, M., DAVIS, M. M., Chien, Y. H. 1991; 174 (1): 293-296

    Abstract

    CD4 and CD8 have been useful surface markers for alpha/beta T cell maturation. In an alpha/beta T cell receptor (TCR) transgenic SCID mice system, it has been shown that alpha/beta TCR alone is sufficient to induce CD4 and CD8 surface expression on thymic T cells. Although the late embryonic thymic gamma/delta T cells are predominately single and double positive, it has not been clear if gamma/delta TCR has a similar capacity. In this study, we show that when transgenes encoding the earliest embryonic gamma/delta TCR are coexpressed with the SCID defect, the gamma/delta transgenes promote the appearance of both the CD4-8- and CD4+8+ T cells in the thymus. Furthermore, the expression of CD4 and CD8 does not require continuous surface gamma/delta TCR expression. These results indicate that gamma/delta TCR alone can promote the CD4/8 surface expression, and may suggest a role for gamma/delta T cells in initiating normal thymic ontogeny.

    View details for Web of Science ID A1991FU89700034

    View details for PubMedID 1905341

  • EXPRESSION OF A FETAL GAMMA-DELTA T-CELL RECEPTOR IN ADULT MICE TRIGGERS A NON-MHC-LINKED FORM OF SELECTIVE DEPLETION INTERNATIONAL IMMUNOLOGY Iwashima, M., Green, A., Bonyhadi, M., DAVIS, M. M., Allison, J. P., Chien, Y. 1991; 3 (4): 385-393

    Abstract

    Day 14 fetal thymocytes and adult dendritic epidermal T cells (dEC) of all mouse strains express a characteristic non-polymorphic gamma delta T-cell receptor which is rarely found in the adult thymus or lymph nodes. We have made transgenic mice expressing this particular set of receptors on T cells in C3H and C57BL/6 mice. In adult mice of the latter strain, a dramatic depletion of transgene expressing T cells occurs and this effect is primarily mediated by thymic radiosensitive cells. The depletion is genetically dominant but not MHC-linked with major factor(s) mapping to chromosome 18. Taken together, our results show that strain-specific developmental changes in the thymic environment may play a role in shaping the gamma delta TCR repertoire.

    View details for Web of Science ID A1991FK38000012

    View details for PubMedID 1831656

  • A DEVELOPMENTAL SWITCH IN THYMIC LYMPHOCYTE MATURATION POTENTIAL OCCURS AT THE LEVEL OF HEMATOPOIETIC STEM-CELLS CELL Ikuta, K., Kina, T., MacNeil, I., Uchida, N., Peault, B., Chien, Y. H., Weissman, I. L. 1990; 62 (5): 863-874

    Abstract

    Hematopoietic stem cells (HSCs) isolated from mouse fetal liver, like adult HSCs, are Thy-1lo Lin- Sca-1+. Donor-derived V gamma 3+ T cells were detected in fetal thymic lobes repopulated in vitro with fetal liver HSCs, but not in those with adult bone marrow HSCs. Single clonogenic fetal HSCs gave rise to thymic progeny that include V gamma 3+, other gamma delta+, and alpha beta+ T cells. No V gamma 3+ T cells were detected in adult thymus injected intrathymically with either fetal or adult HSCs. These results support the hypothesis that only fetal HSCs have the capacity to differentiate into V gamma 3+ T cells in the fetal thymic microenvironment and that the developmental potential of HSCs may change during ontogeny.

    View details for Web of Science ID A1990DY10000006

    View details for PubMedID 1975515

  • A POSSIBLE BASIS FOR MAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED T-CELL RECOGNITION PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES DAVIS, M. M., Chien, Y. H., BJORKMAN, P. J., ELLIOTT, J. F., Iwashima, M., ROCK, E. P., PATTEN, P. A. 1989; 323 (1217): 521-524

    Abstract

    Four distinct T-cell antigen-receptor gene loci have now been identified and partly characterized: alpha, beta, gamma and delta. All of these loci can rearrange in an immunoglobulin-like fashion and express polypeptides that contribute to either alpha:beta or gamma:delta T-cell receptor-CD3 complexes. Surprisingly, the T-cell receptor (TCR) delta coding regions are located entirely, or almost entirely, within the TCR alpha locus and share at least some of the V region gene segments, thus at least partly linking the two different types of receptor heterodimers. Analysis of potential T-cell receptor diversity, particularly that of the delta chain, indicates a striking concentration of somatic polymorphism in the V-J junctional region of the two heterodimers, four to six orders of magnitude higher than similar calculations for immunoglobulin light- and heavy-chain combinations. In contrast, the number of possible V region combinations in T-cell receptors is one hundredth to one thousandth that of immunoglobulins. TCR alpha: beta heterodimers are known to recognize many possible fragments of antigens embedded in the peptide-binding clefts of a relatively small number of major histocompatibility complex (MHC) molecules. Thus it is attractive to speculate that the V-J junctional portions of both types of T-cell receptor contact peptide antigens, whereas the remaining diversity regions contact the MHC. This contention is supported by molecular modelling studies and has interesting implications for the evolution of antigen-receptor genes.

    View details for Web of Science ID A1989AB41200008

    View details for PubMedID 2569209

  • VARIABLE REGION (V-SIGMA) GENE SEGMENT MOST FREQUENTLY UTILIZED IN ADULT THYMOCYTES IS 3' OF THE CONSTANT (C-SIGMA) REGION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Iwashima, M., Green, A., DAVIS, M. M., Chien, Y. H. 1988; 85 (21): 8161-8165

    Abstract

    A variable region (V delta 5) of the T-cell receptor (TcR) delta chain that is preferentially expressed in adult murine thymocytes is located 2.5 kilobases 3' of the constant region (C delta) element. The V delta 5 coding sequence is in a transcriptional orientation opposite the J delta (joining region) and C delta coding elements and rearranges by inversion. The C delta is divided into four exons, three of which encode amino acids of TcR delta polypeptide, and the fourth comprises the entire 3' untranslated region. In this respect, C delta resembles C alpha rather than C beta or C gamma.

    View details for Web of Science ID A1988Q834100070

    View details for PubMedID 3263646

  • THE ADULT T-CELL RECEPTOR DELTA-CHAIN IS DIVERSE AND DISTINCT FROM THAT OF FETAL THYMOCYTES NATURE ELLIOTT, J. F., ROCK, E. P., PATTEN, P. A., DAVIS, M. M., Chien, Y. H. 1988; 331 (6157): 627-631

    Abstract

    T lymphocytes recognize foreign molecules using the T-cell receptor (TCR), a disulphide-linked heterodimer closely associated with the CD3 polypeptide complex on the cell surface. The TCR alpha beta heterodimers seem largely responsible for the recognition properties of both helper (TH) and cytotoxic (TC) T cells. Recently, a second CD3-associated T-cell receptor heterodimer, gamma delta, has been described. Cells bearing the gamma delta receptor appear before those bearing alpha beta during thymic ontogeny and persist as a minor component (1-10%) of mature peripheral T cells. Their function is unknown. As there are a limited number of functional TCR V gamma gene segments, the size and potential diversity of the V delta repertoire is important for the number of different antigens that may be recognized by gamma delta heterodimers. The delta-chain locus is located 75 kilobases (kb) 5' to the TCR C alpha coding region, raising the possibility that the alpha and delta V-region repertoires may overlap. Also, analysis of rearrangements at the delta-chain locus in developing thymocytes shows distinct fetal and adult patterns indicating that there may be differences between the fetal and adult V delta repertoires. To address these questions, we have characterized a large number of delta-containing complementary DNA clones from adult double-negative thymocytes (CD4-8-), an immature population that is enriched for gamma delta-bearing cells. We find that a limited number of V delta sequences are used, showing little overlap with known adult V alpha s and differing significantly from fetal V delta s. But as two D elements may participate simultaneously in V delta gene assembly, and random nucleotides may be added at any one of three junctional points, the potential number of different delta chains that can be made in the adult thymus is very large (approximately 10(13)).

    View details for Web of Science ID A1988M118000061

    View details for PubMedID 2963227

  • T-CELL RECEPTOR DELTA-GENE REARRANGEMENTS IN EARLY THYMOCYTES NATURE Chien, Y. H., Iwashima, M., Wettstein, D. A., Kaplan, K. B., ELLIOTT, J. F., Born, W., DAVIS, M. M. 1987; 330 (6150): 722-727

    Abstract

    The T-cell receptor delta-chain variable region can be assembled from as many as four distinct gene segments, V, D1, D2 and J, more than any other antigen-receptor gene. In fetal thymocytes V----D joinings are as common as D----J or VDJ rearrangements and one V gene segment predominates. Analysis of rearrangements at TCR gamma and delta loci during fetal ontogeny suggests abrupt changes and possible coordinate control in the rearrangement and expression of these loci.

    View details for Web of Science ID A1987L431600058

    View details for PubMedID 2961997

  • IDENTIFICATION AND SEQUENCE OF A 4TH HUMAN T-CELL ANTIGEN RECEPTOR CHAIN NATURE Loh, E. Y., Lanier, L. L., Turck, C. W., Littman, D. R., DAVIS, M. M., Chien, Y. H., WEISS, A. 1987; 330 (6148): 569-572

    Abstract

    Thymus-derived lymphocytes (T cells) use clonally distributed antigen receptors to recognize peptide fragments associated with products of the major histocompatibility complex (MHC) (refs 1-4). On most murine and human T cells the T cell receptor (TCR) is composed of disulphide-linked alpha and beta chains (TCR alpha/beta), each of which contains constant and variable domains, and which are associated with the invariant chains of the CD3 complex. It has been demonstrated, however, that a distinct CD3-associated TCR is expressed on a small subset of T cells or immature thymocytes which fail to express either CD4 or CD8 (refs 7-14), the molecules associated with class II or class I MHC antigen recognition. Instead of TCR alpha/beta, these cells express heterodimers of gamma and delta chains (TRC gamma/delta). The genes encoding alpha, beta, and gamma have been isolated and characterized. A new murine T cell receptor (Cx) gene which undergoes rearrangement and expression early during T cell ontogeny has recently been identified 5' of the murine J alpha C alpha gene locus. Here we isolate and sequence the homologous transcript from PEER, a human cell line that expresses a TCR gamma/delta, and show that it encodes a protein with characteristic V, D, J, and C segments. Using probes derived from this transcript, we have shown that both PEER and MOLT-13, another TCR gamma/delta-expressing cell line, rearrange this locus and express two sizes of transcripts differing in the 3' untranslated region. Using a synthetic peptide derived from the deduced C region sequence, we have prepared antisera that precipitates the delta chain of the TCR from both PEER and MOLT-13, thus demonstrating that Cx and its human homologue code for the delta chain of the TCR.

    View details for Web of Science ID A1987L184100062

    View details for PubMedID 2825032

  • A NEW T-CELL RECEPTOR GENE LOCATED WITHIN THE ALPHA-LOCUS AND EXPRESSED EARLY IN T-CELL DIFFERENTIATION NATURE Chien, Y. H., Iwashima, M., Kaplan, K. B., ELLIOTT, J. F., DAVIS, M. M. 1987; 327 (6124): 677-682

    Abstract

    A new T-cell receptor gene lies just 5' to the J alpha C alpha coding regions. Its placement in this location suggests a novel mechanism for the regulation of expression of one T-cell receptor polypeptide to another during ontogeny. Rearrangement of this locus occurs very early in thymic differentiation and its RNA expression parallels that of the gamma-chain in thymic subpopulations, making this a possible candidate for the recently described delta-chain of the T-cell receptor.

    View details for Web of Science ID A1987H882700046

    View details for PubMedID 2439914

Conference Proceedings


  • Visualizing T-cell recognition DAVIS, M. M., Wulfing, C., Krummel, M. F., Savage, P. A., Xu, J., Sumen, C., Dustin, M. L., Chien, Y. H. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. 1999: 243-251

    View details for Web of Science ID 000087225400030

    View details for PubMedID 11232292

  • Biological and chemical aspects of T-cell receptor-mediated recognition DAVIS, M. M., Lyons, D. S., Altman, J. D., Hampl, J., BONIFACE, J. J., Arden, B., Chien, Y. MUNKSGAARD. 1997: 193-203
  • ISSUES CONCERNING THE NATURE OF ANTIGEN RECOGNITION BY ALPHA-BETA AND GAMMA-DELTA T-CELL RECEPTORS DAVIS, M. M., Chien, Y. H. ELSEVIER SCI LTD. 1995: 316-318

    View details for Web of Science ID A1995RG98300006

    View details for PubMedID 7576062

  • T-CELL RECEPTOR V-REGION USAGE AND ANTIGEN-SPECIFICITY - THE CYTOCHROME-C MODEL SYSTEM DAVIS, M. M., MCHEYZERWILLIAMS, M., Chien, Y. H. NEW YORK ACAD SCIENCES. 1995: 1-11

    Abstract

    Investigations of the I-Ek-restricted, cytochrome c-specific T-cell response in mice show that both T-cell receptor V alpha and V beta CDR3 residues and the use of particular V alpha s and V beta s are necessary for recognition. Data strongly suggest that specific CDR3 residues are important in contacting the peptide. Other experiments indicate that the requirement for V alpha:V beta conservation is not the result of strong TCR-->MHC interactions, as no correlation was found between V beta usage and changes in the alpha-helixes of the I-Ek molecule. It is also apparent that changes in V alpha or V beta usage could be elicited by changes in the side chain size of single amino acids of the antigenic peptides, suggesting that V alpha or V beta conservation is important for peptide recognition, either directly or indirectly. We also show that we can follow the cytochrome c response in vivo even in nontransgenic mice, solely by staining with anti-V region antibodies as well as mAbs directed at the activation markers CD44 and L-selectin.

    View details for Web of Science ID A1995BD46M00001

    View details for PubMedID 7645810

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