Bio

Education & Certifications


  • PhD, University of Pennsylvania, Immunology (2004)
  • MPH, UMDNJ-Robert Wood Johnson Medical School, Public Health Policy and Education (1993)
  • BS, Ithaca College, Exercise Physiology (1990)

Professional

Work Experience


  • Post-doctoral Fellow, Schering Plough Biopharma (10/5/2006)

    Studies involved investigation of the IL-23 signaling pathway on both innate and adaptive lymphocyte populations; and exploration
    of novel myeloid receptor biology, both through the use of in vivo infectious disease and inflammatory models, such as EAE, CIA and IBD.
    Co-inventor on multiple patent applications.

    Location

    Palo Alto, CA

  • Graduate Work, University of Pennsylvania (7/1/2000)

    My research investigated how the nuclear factor−κB (NF-κB) family of transcription factors mediate resistance to infection with the protozoan parasite, Toxoplasma gondii. In addition to demonstrating the dependence of CD4+ T cells on NF-κB for antigen specific effector cell expansion and IFN-γ production, my studies also revealed a novel role for two members, p50 and c-Rel, in the regulation of IFN−γ production in natural killer (NK) cells.

    Location

    Philadelphia, PA

Publications

Journal Articles


  • How the immune system talks to itself: the varied role of synapses IMMUNOLOGICAL REVIEWS Xie, J., Tato, C. M., Davis, M. M. 2013; 251: 65-79

    Abstract

    Using an elaborately evolved language of cytokines and chemokines as well as cell-cell interactions, the different components of the immune system communicate with each other and orchestrate a response (or wind one down). Immunological synapses are a key feature of the system in the ways in which they can facilitate and direct these responses. Studies analyzing the structure of an immune synapse as it forms between two cells have provided insight into how the stability and kinetics of this interaction ultimately affect the sensitivity, potency, and magnitude of a given response. Furthermore, we have gained an appreciation of how the immunological synapse provides directionality and contextual cues for downstream signaling and cellular decision-making. In this review, we discuss how using a variety of techniques, developed over the last decade, have allowed us to visualize and quantify key aspects of the dynamic synaptic interface and have furthered our understanding of their function. We describe some of the many characteristics of the immunological synapse that make it a vital part of intercellular communication and some of the questions that remain to be answered.

    View details for DOI 10.1111/imr.12017

    View details for Web of Science ID 000317077400006

    View details for PubMedID 23278741

  • The Cytokines Interleukin 27 and Interferon-gamma Promote Distinct Treg Cell Populations Required to Limit Infection-Induced Pathology IMMUNITY Hall, A. O., Beiting, D. P., Tato, C., John, B., Oldenhove, G., Lombana, C. G., Pritchard, G. H., Silver, J. S., Bouladoux, N., Stumhofer, J. S., Harris, T. H., Grainger, J., Wojno, E. D., Wagage, S., Roos, D. S., Scott, P., Turka, L. A., Cherry, S., Reiner, S. L., Cua, D., Belkaid, Y., Elloso, M. M., Hunter, C. A. 2012; 37 (3): 511-523

    Abstract

    Interferon-? (IFN-?) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-? in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-? or IL-27 have distinct transcriptional profiles. Thus, IFN-? and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.

    View details for DOI 10.1016/j.immuni.2012.06.014

    View details for Web of Science ID 000309199000015

    View details for PubMedID 22981537

  • The Myeloid Receptor PILR beta Mediates the Balance of Inflammatory Responses through Regulation of IL-27 Production PLOS ONE Tato, C. M., Joyce-Shaikh, B., Banerjee, A., Chen, Y., Sathe, M., Ewald, S. E., Liu, M., Gorman, D., McClanahan, T. K., Phillips, J. H., Heyworth, P. G., Cua, D. J. 2012; 7 (3)

    Abstract

    Paired immunoglobulin-like receptors beta, PILR?, and alpha, PILR?, are related to the Siglec family of receptors and are expressed primarily on cells of the myeloid lineage. PILR? is a DAP12 binding partner expressed on both human and mouse myeloid cells. The potential ligand, CD99, is found on many cell types, such as epithelial cells where it plays a role in migration of immune cells to sites of inflammation. Pilrb deficient mice were challenged with the parasite Toxoplasma gondii in two different models of infection induced inflammation; one involving the establishment of chronic encephalitis and a second mimicking inflammatory bowel disease in order to understand the potential role of this receptor in persistent inflammatory responses. It was found that in the absence of activating signals from PILR?, antigen-presenting cells (APCs) produced increased amounts of IL-27, p28 and promoted IL-10 production in effector T cells. The sustained production of IL-27 led ultimately to enhanced survival after challenge due to dampened immune pathology in the gut. Similar protection was also observed in the CNS during chronic T. gondii infection after i.p. challenge again providing evidence that PILR? is important for regulating aberrant inflammatory responses.

    View details for DOI 10.1371/journal.pone.0031680

    View details for Web of Science ID 000303894900003

    View details for PubMedID 22479310

  • Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling NATURE Ghoreschi, K., Laurence, A., Yang, X., Tato, C. M., McGeachy, M. J., Konkel, J. E., Ramos, H. L., Wei, L., Davidson, T. S., Bouladoux, N., Grainger, J. R., Chen, Q., Kanno, Y., Watford, W. T., Sun, H., Eberl, G., Shevach, E., Belkaid, Y., Cua, D. J., Chen, W., O'Shea, J. J. 2010; 467 (7318): 967-U144

    Abstract

    CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-?1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-? signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1? effectively induced IL-17 production in naive precursors, independently of TGF-?. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-?1, allowing the generation of cells that co-expressed ROR?t (encoded by Rorc) and T-bet. T-bet(+)ROR?t(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-?1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

    View details for DOI 10.1038/nature09447

    View details for Web of Science ID 000283254700039

    View details for PubMedID 20962846

  • Innate IL-17-producing cells: the sentinels of the immune system NATURE REVIEWS IMMUNOLOGY Cua, D. J., Tato, C. M. 2010; 10 (7): 479-489

    Abstract

    The cytokine interleukin-17 (IL-17) has received considerable attention since the discovery of a distinct CD4(+) T helper (T(H)) cell subset that produces it, known as the T(H)17 cell subset. Despite the fact that most of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an inflammatory response is produced by innate immune cells. In this Review, we explore the many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens. These early sources have been shown to have a central role in the initiation of IL-17-dependent immune responses, even before the first CD4(+)T cell sees its cognate antigen and initiates the T(H)17 cell developmental programme.

    View details for DOI 10.1038/nri2800

    View details for Web of Science ID 000279151100009

    View details for PubMedID 20559326

  • IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells JOURNAL OF IMMUNOLOGY Diveu, C., McGeachy, M. J., Boniface, K., Stumhofer, J. S., Sathe, M., Joyce-Shaikh, B., Chen, Y., Tato, C. M., McClanahan, T. K., Malefyt, R. d., Hunter, C. A., Cua, D. J., Kastelein, R. A. 2009; 182 (9): 5748-5756

    Abstract

    IL-27 is secreted by APCs in response to inflammatory stimuli and exerts a proinflammatory Th1-enhancing activity but also has significant anti-inflammatory functions. We examined the molecular mechanism by which IL-27 regulates TGFbeta plus IL-6- or IL-23-dependent Th17 development in the mouse and human systems. IL-27 inhibited the production of IL-17A and IL-17F in naive T cells by suppressing, in a STAT1-dependent manner, the expression of the Th17-specific transcription factor RORgamma t. The in vivo significance of the role of IL-27 was addressed in delayed-type hypersensitivity response and experimental autoimmune encephalomyelitis (EAE). By generating mice deficient for the p28 subunit of IL-27, we showed that IL-27 regulated the severity of delayed-type hypersensitivity response and EAE through its effects on Th17 cells. Furthermore, up-regulation of IL-10 in the CNS, which usually occurs late after EAE onset and plays a role in the resolution of the disease, was notably absent in IL-27p28(-/-) mice. These results show that IL-27 acts as a negative regulator of the developing IL-17A response in vivo, suggesting a potential therapeutic role for IL-27 in autoimmune diseases.

    View details for DOI 10.4049/jimmunol.0801162

    View details for Web of Science ID 000275119200069

    View details for PubMedID 19380822

  • The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo NATURE IMMUNOLOGY McGeachy, M. J., Chen, Y., Tato, C. M., Laurence, A., Joyce-Shaikh, B., Blumenschein, W. M., McClanahan, T. K., O'Shea, J. J., Cua, D. J. 2009; 10 (3): 314-324

    Abstract

    Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (T(H)-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of T(H)-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, T(H)-17 development was stalled at the early activation stage. T(H)-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor alpha-chain. These defects were associated with less proliferation; consequently, fewer effector T(H)-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.

    View details for DOI 10.1038/ni.1698

    View details for Web of Science ID 000263456500016

    View details for PubMedID 19182808

  • Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22 JOURNAL OF EXPERIMENTAL MEDICINE Takatori, H., Kanno, Y., Watford, W. T., Tato, C. M., Weiss, G., Ivanov, I. I., Littman, D. R., O'Shea, J. J. 2009; 206 (1): 35-41

    Abstract

    The interleukin (IL) 17 family of cytokines has emerged to be critical for host defense as well as the pathogenesis of autoimmune and autoinflammatory disorders, and serves to link adaptive and innate responses. Recent studies have identified a new subset of T cells that selectively produce IL-17 (Th17 cells; Bettelli, E., T. Korn, and V.K. Kuchroo. 2007. Curr. Opin. Immunol. 19:652-657; Kolls, J.K., and A. Linden. 2004. Immunity. 21:467-476), but the regulation of IL-17 production by innate immune cells is less well understood. We report that in vitro stimulation with IL-23 induced IL-17 production by recombination activating gene (Rag) 2(-/-) splenocytes but not Rag2(-/-) common gamma chain(-/-) splenocytes. We found that a major source of IL-17 was CD4(+)CD3(-)NK1.1(-)CD11b(-)Gr1(-)CD11c(-)B220(-) cells, a phenotype that corresponds to lymphoid tissue inducer-like cells (LTi-like cells), which constitutively expressed the IL-23 receptor, aryl hydrocarbon receptor, and CCR6. In vivo challenge with the yeast cell wall product zymosan rapidly induced IL-17 production in these cells. Genetic deletion of signal transducer and activator of transcription 3 reduced but did not abrogate IL-17 production in LTi-like cells. Thus, it appears that splenic LTi-like cells are a rapid source of IL-17 and IL-22, which might contribute to dynamic organization of secondary lymphoid organ structure or host defense.

    View details for DOI 10.1084/jem.20072713

    View details for Web of Science ID 000266008300006

    View details for PubMedID 19114665

  • Alternative lifestyles of T cells NATURE IMMUNOLOGY Tato, C. M., Cua, D. J. 2008; 9 (12): 1323-1325

    View details for DOI 10.1038/ni1208-1323

    View details for Web of Science ID 000260888700003

    View details for PubMedID 19008928

  • Reconciling id, ego, and superego within interleukin-23 IMMUNOLOGICAL REVIEWS Tato, C. M., Cua, D. J. 2008; 226: 103-111

    Abstract

    The study of interleukin-23 (IL-23) over the past 8 years has led to the realization that cellular immunity is far more complex than previously appreciated, because it is controlled by additional newly identified players. From the analysis of seemingly straightforward cytokine regulation of autoimmune diseases, many limitations of the established paradigms emerged that required reevaluation of the 'rules' that govern the initiation and maintenance of immune responses. This information led to a major revision of the T-helper 1 (Th1)/Th2 hypothesis and discovery of an unexpected link between transforming growth factor-beta-dependent Th17 and inducible regulatory T cells. The aim of this review is to explore the multiple characteristics of IL-23 with respect to its 'id' in autoimmunity, 'ego' in T-cell help, and 'superego' in defense against mucosal pathogens.

    View details for Web of Science ID 000260538100009

    View details for PubMedID 19161419

  • Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii JOURNAL OF EXPERIMENTAL MEDICINE Watford, W. T., Hissong, B. D., Durant, L. R., Yamane, H., Muul, L. M., Kanno, Y., Tato, C. M., Ramos, H. L., Berger, A. E., Mielke, L., Pesu, M., Solomon, B., Frucht, D. M., Paul, W. E., Sher, A., Jankovic, D., Tsichlis, P. N., O'Shea, J. J. 2008; 205 (12): 2803-2812

    Abstract

    Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.

    View details for DOI 10.1084/jem.20081461

    View details for Web of Science ID 000261295300014

    View details for PubMedID 19001140

  • SnapShot: Cytokines IV. Cell Tato, C. M., Cua, D. J. 2008; 132 (6): 1062 e1-2

    View details for DOI 10.1016/j.cell.2008.02.024

    View details for PubMedID 18358817

  • SnapShot: Cytokines III CELL Tato, C. M., Cua, D. J. 2008; 132 (5): 900-U12

    View details for DOI 10.1016/j.cell.2008.02.023

    View details for Web of Science ID 000253818000025

    View details for PubMedID 18329374

  • SnapShot: cytokines II. Cell Tato, C. M., Cua, D. J. 2008; 132 (3): 500-?

    View details for DOI 10.1016/j.cell.2008.01.002

    View details for PubMedID 18267079

  • SnapShot: Cytokines I CELL Tato, C. M., Cua, D. J. 2008; 132 (2)

    View details for DOI 10.1016/j.cell.2008.01.001

    View details for Web of Science ID 000253427700017

    View details for PubMedID 18243106

  • TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology NATURE IMMUNOLOGY McGeachy, M. J., Bak-Jensen, K. S., Chen, Y., Tato, C. M., Blumenschein, W., McClanahan, T., Cua, D. J. 2007; 8 (12): 1390-1397

    Abstract

    Studies have shown that transforming growth factor-beta (TGF-beta) and interleukin 6 (IL-6) are required for the lineage commitment of pathogenic IL-17-producing T helper cells (T(H)-17 cells). Unexpectedly, here we found that stimulation of myelin-reactive T cells with TGF-beta plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. Cells stimulated with TGF-beta plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. Hence, TGF-beta and IL-6 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of T(H)-17 cells. Our findings suggest that full acquisition of pathogenic function by effector T(H)-17 cells is mediated by IL-23 rather than by TGF-beta and IL-6.

    View details for DOI 10.1038/ni1539

    View details for Web of Science ID 000251267000020

    View details for PubMedID 17994024

  • Distinct regulation of interleukin-17 in human T helper lymphocytes ARTHRITIS AND RHEUMATISM Chen, Z., Tato, C. M., Muul, L., Laurence, A., O'Shea, J. J. 2007; 56 (9): 2936-2946

    Abstract

    Interleukin-17 (IL-17)-producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid-related orphan receptor gammat (RORgammat). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive human CD4+ T cells of cytokines known to promote murine Th17 cells.Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction.In response to anti-CD3/anti-CD28 stimulation alone, human memory T cells rapidly produced IL-17, whereas naive T cells expressed low levels. Transforming growth factor beta1 and IL-6 up-regulated RORgammat expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL-23 up-regulated its own receptor and was an important inducer of IL-17 and IL-22.The present data demonstrate the differential regulation of IL-17 and RORgammat expression in human CD4+ T cells compared with murine cells. Optimal conditions for the development of IL-17-producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL-23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.

    View details for DOI 10.1002/art.22866

    View details for Web of Science ID 000249832600015

    View details for PubMedID 17763419

  • Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation IMMUNITY Laurence, A., Tato, C. M., Davidson, T. S., Kanno, Y., Chen, Z., Yao, Z., Blank, R. B., Meylan, F., Siegel, R., Hennighausen, L., Shevach, E. M., O'Shea, J. J. 2007; 26 (3): 371-381

    Abstract

    Recent work has identified a new subset of effector T cells that produces interleukin (IL)-17 known as T helper 17 (Th17) cells, which is involved in the pathophysiology of inflammatory diseases and is thought to be developmentally related to regulatory T (Treg) cells. Because of its importance for Treg cells, we examined the role of IL-2 in Th17 generation and demonstrate that a previously unrecognized aspect of IL-2 function is to constrain IL-17 production. Genetic deletion or antibody blockade of IL-2 promoted differentiation of the Th17 cell subset. Whereas STAT3 appeared to be a key positive regulator of RORgammat and IL-17 expression, absence of IL-2 or disruption of its signaling by deletion of the transcription factor STAT5 resulted in enhanced Th17 cell development. We conclude that in addition to the promotion of activation-induced cell death of lymphocytes and the generation of Treg cells, inhibition of Th17 polarization appears to be an important function of IL-2.

    View details for DOI 10.1016/j.immuni.2007.02.009

    View details for Web of Science ID 000245228100013

    View details for PubMedID 17363300

  • Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals JOURNAL OF EXPERIMENTAL MEDICINE Villarino, A. V., Tato, C. M., Stumhofer, J. S., Yao, Z., Cui, Y. K., Hennighausen, L., O'Shea, J. J., Hunter, C. A. 2007; 204 (1): 65-71

    Abstract

    Although required for many fundamental immune processes, ranging from self-tolerance to pathogen immunity, interleukin (IL)-2 production is transient, and the mechanisms underlying this brevity remain unclear. These studies reveal that helper T cell IL-2 production is limited by a classic negative feedback loop that functions autonomously or in collaboration with other common gamma chain (IL-4 and IL-7) and IL-6/IL-12 family cytokines (IL-12 and IL-27). Consistent with this model for cytokine-dependent regulation, they also demonstrate that the inhibitory effect can be mediated by several signal transducer and activator of transcription (STAT) family transcription factors, namely STAT5, STAT4, and STAT6. Collectively, these findings establish that IL-2 production is limited by a network of autocrine and paracrine signals that are readily available during acute inflammatory responses and, thus, provide a cellular and molecular basis for its transient pattern of expression.

    View details for DOI 10.1084/jem.20061198

    View details for Web of Science ID 000243753600011

    View details for PubMedID 17227909

  • Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system NATURE IMMUNOLOGY Stumhofer, J. S., Laurence, A., Wilson, E. H., Huang, E., Tato, C. M., Johnson, L. M., Villarino, A. V., Huang, Q., Yoshimura, A., Sehy, D., Saris, C. J., O'Shea, J. J., Hennighausen, L., Ernst, M., Hunter, C. A. 2006; 7 (9): 937-945

    Abstract

    Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize T(H)-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development T(H)-17 cells induced by IL-6 and transforming growth factor-beta, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of T(H)-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

    View details for DOI 10.1038/ni1376

    View details for Web of Science ID 000239942300012

    View details for PubMedID 16906166

  • Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chen, Z., Laurence, A., Kanno, Y., Pacher-Zavisin, M., Zhu, B., Tato, C., Yoshimura, A., Hennighausen, L., O'Shea, J. J. 2006; 103 (21): 8137-8142

    Abstract

    Suppressor of cytokine signaling (Socs) 3 is a cytokine-inducible inhibitor with critical but selective cell-specific effects. We show that deficiency of Socs3 in T cells had minimal effects on differentiation of T cells to the T helper (Th) 1 or Th2 subsets; accordingly, Socs3 had no effect on IL-12-dependent signal transducer and activator of transcription (Stat) 4 phosphorylation or IL-4-dependent Stat6 phosphorylation. By contrast, Socs3 was found to be a major regulator of IL-23-mediated Stat3 phosphorylation and Th17 generation, and Stat3 directly binds to the IL-17A and IL-17F promoters. We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation.

    View details for DOI 10.1073/pnas.0600666103

    View details for Web of Science ID 000237853900037

    View details for PubMedID 16698929

  • Immunology - What does it mean to be just 17? NATURE Tato, C. M., O'Shea, J. J. 2006; 441 (7090): 166-168

    View details for DOI 10.1038/441166a

    View details for Web of Science ID 000237418800030

    View details for PubMedID 16688162

  • Helper T cell differentiation enters a new era: Le Roi est mort; vive le Roi! JOURNAL OF EXPERIMENTAL MEDICINE Tato, C. M., Laurence, A., O'Shea, J. J. 2006; 203 (4): 809-812

    Abstract

    In the dark ages of T cell biology, we considered two fates for differentiated CD4+ T cells: T helper (Th)1 and Th2 cells. Now we know that the reality is much more complex and interesting. The newest Th cell subset produces the cytokine IL-17. New evidence shows that the IL-17-related cytokine IL-25 is essential for Th2 responses in two infectious disease models.

    View details for DOI 10.1084/jem.20060522

    View details for Web of Science ID 000237056000003

    View details for PubMedID 16606679

  • Opposing roles of NF-kappa B family members in the regulation of NK cell proliferation and production of IFN-gamma INTERNATIONAL IMMUNOLOGY Tato, C. M., Mason, N., Artis, D., Shapira, S., Caamano, J. C., Bream, J. H., Liou, H. C., Hunter, C. A. 2006; 18 (4): 505-513

    Abstract

    It is well established that the nuclear factor-kappaB (NF-kappaB) family of transcription factors participates in the regulation of many aspects of innate and adaptive immunity. The majority of these reports have focused on the role of NF-kappaB in accessory cell and T or B cell function, but less is known about the role of NF-kappaB in NK cells. However, several studies have demonstrated that these transcription factors are required for NK cell production of IFN-gamma and proliferation. The studies presented here examine the role of two NF-kappaB members, c-Rel and p50, in NK cell function. In vitro data revealed that in the absence of c-Rel, NK cells have a defect in their ability to secrete IFN-gamma, but remain unaffected in their capacity to proliferate. In contrast, p50-/- NK cells have enhanced proliferative and IFN-gamma responses compared with wild-type NK cells. The latter findings suggest a role for p50 as a negative regulator of NK cell production of IFN-gamma and chromatin immunoprecipitation assays demonstrated the association of p50 with the IFN-gamma promoter of resting NK cells. Consistent with the in vitro studies, in vivo studies with NF-kappaB gene-deficient mice infected with Toxoplasma gondii revealed that the absence of p50 leads to enhanced NK cell proliferation and production of IFN-gamma. Together, these studies define distinct roles for c-Rel and p50 in the function of NK cells.

    View details for DOI 10.1093/intimm/dxh391

    View details for Web of Science ID 000236253700002

    View details for PubMedID 16481345

  • Cutting edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter JOURNAL OF IMMUNOLOGY Tato, C., Martins, G. A., High, F. A., DiCioccio, C. B., Reiner, S. L., Hunter, C. A. 2004; 173 (3): 1514-1517

    Abstract

    The ability of NK and T cells to produce IFN-gamma is critical for resistance to numerous intracellular pathogens but the kinetics of these responses differ. Consistent with this is a requirement for naive T cells to become activated and undergo proliferation-dependent epigenetic changes to the IFN-gamma locus that allow them to produce IFN-gamma. The data presented here reveal that unlike T cells, murine NK cells produce IFN-gamma under conditions of short-term cytokine stimulation, and these events are independent of proliferation and cell cycle progression. Furthermore, analysis of the IFN-gamma locus in NK cells reveals that this locus is constitutively demethylated. The finding that NK cells do not need to remodel the IFN-gamma locus to produce IFN-gamma, either because they do not exhibit epigenetic repression or they have undergone prior remodeling during development, provides a molecular basis for the innate and adaptive regulation of the production of this cytokine.

    View details for Web of Science ID 000222807100005

    View details for PubMedID 15265878

  • The regulation and activation of CD44 by natural killer (NK) cells and its role in the production of IFN-gamma JOURNAL OF INTERFERON AND CYTOKINE RESEARCH Sague, S. L., Tato, C., Pure, E., Hunter, C. A. 2004; 24 (5): 301-309

    Abstract

    Natural killer (NK) cells can express high levels of CD44, and signaling through CD44 has been shown to enhance NK cell cytotoxic activity. However, little is known about the factors that regulate CD44-mediated activation of NK cells. The studies reported here reveal that resting NK cells constitutively express CD44 that is in an inactive form that does not bind to hyaluronan (HA), the principal known ligand for CD44. After infection of mice with the intracellular parasite Toxoplasma gondii, however, a population of NK cells that expressed activated CD44 emerged. To determine how expression and activation of CD44 by resting NK cells were regulated, the role of cytokines in these events was assessed. These studies revealed that whereas stimulation of resting NK cells with interleukin-12 (IL-12) or IL-18 caused increased expression of CD44, only IL-2 or IL-15 led to the upregulation and activation of CD44. The cytokine-induced upregulation and activation of CD44 was independent of NK cell proliferation. To determine the functional consequences of CD44 activation, the effects of low molecular weight HA (LMWHA) on the production of interferon-gamma (IFN-gamma) by IL-2-activated NK cells were assessed. These studies showed that HA alone had little effect on the production of IFN-gamma, but when used in combination with IL-2, IL-12, or IL-18, LMWHA was a potent enhancer of IFN-gamma production. Together, these studies indicate an important role for proinflammatory cytokines in the activation of CD44 on NK cells and identify a novel pathway to enhance the ability of activated NK cells to produce IFN-gamma.

    View details for Web of Science ID 000221465700005

    View details for PubMedID 15153314

  • Inhibition of NF-kappa B activity in T and NK cells results in defective effector cell expansion and production of IFN-gamma required for resistance to Toxoplasma gondii JOURNAL OF IMMUNOLOGY Tato, C. M., Villarino, A., Caamano, J. H., Boothby, M., Hunter, C. A. 2003; 170 (6): 3139-3146

    Abstract

    To define the role of NF-kappa B in the development of T cell responses required for resistance to Toxoplasma gondii, mice in which T cells are transgenic for a degradation-resistant (Delta N) form of I kappa B alpha, an inhibitor of NF-kappa B, were challenged with T. gondii and their response to infection compared with control mice. I kappa B alpha(Delta N)-transgenic (Tg) mice succumbed to T. gondii infection between days 12 and 35, and death was associated with an increased parasite burden compared with wild-type (Wt) controls. Analysis of the responses of infected mice revealed that IL-12 responses were comparable between strains, but Tg mice had a marked reduction in systemic levels of IFN-gamma, the major mediator of resistance to T. gondii. In addition, the infection-induced increase in NK cell activity observed in Wt mice was absent from Tg mice and this correlated with NK cell expression of the transgene. Infection-induced activation of CD4(+) T cells was similar in Wt and Tg mice, but expansion of activated CD4(+)T cells was markedly reduced in the Tg mice. This difference in T cell numbers correlated with a reduced capacity of these cells to proliferate after stimulation and was associated with a major defect in the ability of CD4(+) T cells from infected mice to produce IFN-gamma. Together, these studies reveal that inhibition of NF-kappa B activity in T and NK cells results in defective effector cell expansion and production of IFN-gamma required for resistance to T. gondii.

    View details for Web of Science ID 000181412500046

    View details for PubMedID 12626571

  • Costimulation in resistance to infection and development of immune pathology - Lessons from toxoplasma IMMUNOLOGIC RESEARCH Hunter, C. A., Lieberman, L. A., Mason, N., Pepper, M., Sague, S. L., Tato, C., Zediak, V. 2003; 27 (2-3): 331-339

    Abstract

    Parasitic infections remain an important cause of disease worldwide, and it is important to understand how the immune system protects against these organisms. In addition, the study of how the immune system deals with different types of pathogens provides the opportunity to discern how innate and adaptive arms of the immune system interact to provide an integrated protective response. Costimulatory signals are an important element involved in the control of lymphocyte response, and this laboratory studies the role of the costimulatory molecules CD28 and ICOS in the events that lead to resistance to the opportunistic pathogen Toxoplasma gondii as well as the development of immune pathology associated with this infection.

    View details for Web of Science ID 000184477500019

    View details for PubMedID 12857979

  • Host-pathogen interactions: Subversion and utilization of the NF-kappa B pathway during infection INFECTION AND IMMUNITY Tato, C. M., Hunter, C. A. 2002; 70 (7): 3311-3317
  • Identification of a role for NF-kappa B2 in the regulation of apoptosis and in maintenance of T cell-mediated immunity to Toxoplasma gondii JOURNAL OF IMMUNOLOGY Caamano, J., Tato, C., Cai, G. F., Villegas, E. N., Speirs, K., Craig, L., Alexander, J., Hunter, C. A. 2000; 165 (10): 5720-5728

    Abstract

    The NF-kappaB family of transcription factors are involved in the regulation of innate and adaptive immune functions associated with resistance to infection. To assess the role of NF-kappaB(2) in the regulation of cell-mediated immunity, mice deficient in the NF-kappaB(2) gene (NF-kappaB(2)(-/-)) were challenged with the intracellular parasite Toxoplasma gondii. Resistance to this opportunistic pathogen is dependent on the production of IL-12, which is required for the development of innate NK cell and adaptive T cell responses dominated by the production of IFN-gamma necessary to control replication of this parasite. Although wild-type controls were resistant to T. gondii, NF-kappaB(2)(-/-) mice developed severe toxoplasmic encephalitis and succumbed to disease between 3 and 10 wk following infection. However, NF-kappaB(2) was not required for the ability of macrophages to produce IL-12 or to inhibit parasite replication and during the acute stage of infection, NF-kappaB(2)(-/-) mice had no defect in their ability to produce IL-12 or IFN-gamma and infection-induced NK cell responses appeared normal. In contrast, during the chronic phase of the infection, susceptibility of NF-kappaB(2)(-/-) mice to toxoplasmic encephalitis was associated with a reduced capacity of their splenocytes to produce IFN-gamma associated with a loss of CD4(+) and CD8(+) T cells. This loss of T cells correlated with increased levels of apoptosis and with elevated expression of the pro-apoptotic molecule Fas by T cells from infected NF-kappaB(2)(-/-) mice. Together, these results suggest a role for NF-kappaB(2) in the regulation of lymphocyte apoptosis and a unique role for this transcription factor in maintenance of T cell responses required for long-term resistance to T. gondii.

    View details for Web of Science ID 000165254600044

    View details for PubMedID 11067930

  • Listeria monocytogenes as a probe to study cell-mediated immunity CURRENT OPINION IN IMMUNOLOGY Shen, H., Tato, C. M., Fan, X. 1998; 10 (4): 450-458

    Abstract

    The intracellular bacterium Listeria monocytogenes continues to serve as a model to define general paradigms of cell-mediated immunity. Genetic manipulations of the bacterium and its murine host have allowed us to begin dissecting the intricate interactions between this bacterium and the immune system. As a result, we have gained new insights into the mechanisms of immune surveillance, achieved better understanding of bacterial tactics for immune evasion and developed novel strategies in vaccine development.

    View details for Web of Science ID 000075406500014

    View details for PubMedID 9722922

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