Distinct Effects of T-bet in T
            <sub>H</sub>
            1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells

Szabo, Susanne J.; Sullivan, Brandon M.; Stemmann, Claudia; Satoskar, Abhay R.; Sleckman, Barry P.; Glimcher, Laurie H.

doi:10.1126/science.1065543

Cited by 1,061 publications

(1,040 citation statements)

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“…The transcription factor t-bet was essential for optimal IFN-+ -production by CD4 + T cells and NK cells, but not by CD8 + T cells [5]. In a study with wild-type and STAT4-deficient DO11.10 TCR-transgenic mice TCR-/anti-CD28-mediated activation of CD4 + , but not of CD8 + T cells, required the STAT4 transcription factor [8].…”

Section: Tyk2 and T Cellsmentioning

confidence: 99%

“…Cell transfer and depletion studies, the use of neutralizing antibodies and the availability of gene-deficient mouse strains have helped to define cell types, cytokines, effector mechanisms and transcription factors that contribute to the killing or containment of L. major, the clinical healing of the acute skin lesions, and the long-term control of residual parasites persisting in the tissue. These include NK cells, CD4 + Th1 cells, IFN-+ -producing CD8 + T cells, IL-12, IFN-+ , TNF, inducible nitric oxide synthase (iNOS, NOS2) and NADPH oxidase, signal transducer and activator of transcription 4 (STAT4), interferon regulatory factors (IRF)-1 and 2, and T-bet [1][2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Control of Leishmania major in the absence of Tyk2 kinase

et al. 2004

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IL‐12 is indispensable for the control of many intracellular pathogens, but the components of the signaling pathway that are essential for its function in vivo are incompletely understood. Here, we investigated in the Leishmania major mouse model whether Tyk2 kinase is required for the generation of a protective immune response. Unlike C57BL/6 controls, Tyk2–/–mice developed severe skin lesions after infection that frequently ulcerated, but ultimately healed. NK cell cytotoxicity was absent in infected Tyk2–/– mice, even after IL‐12 pretreatment, which correlated with a STAT4 activation defect. IFN‐α / β, which was still able to activate STAT1 in Tyk2–/– NK cells, reconstituted their cytotoxic activity, but not their IL‐12responsiveness. The IL‐12‐induced production of IFN‐γ by NK cells and CD8+ T cells was strongly suppressed in Tyk2–/– mice at day 1 of infection, but partly regained during the late phase of infection. Tyk2–/– CD4+ T cells developed into Th1 cells (although in a delayed fashion) and infected Tyk2–/– mice expressed normals levels of inducible NO synthase. Thus, Tyk2 is required for the IL‐12 response of NK cells and CD8+ T cells in L. major‐infected mice, but not for the generation of Th1 cells and the ultimate control of the disease.

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Section: Tyk2 and T Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Control of Leishmania major in the absence of Tyk2 kinase

et al. 2004

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“…1,2 T-bet belongs to a family of transcription factors, the members of which share a highly conserved DNA-binding domain T-box, flanked by diverse non-DNA-binding domains, which are involved in transactivation or repression. [3][4][5][6] A series of studies in vitro and in vivo showed that T-bet is induced by the T-cell receptor and the IFN-gR/STAT1 signaling pathway in antigen-recognizing naive CD4 þ T cells. The elevated T-bet induces IL-12Rb2 and IFN-g expression, allowing IL-12R/STAT4 signaling to optimize IFN-g expression, and thereby amplifying and establishing the effector commitment of Th1 cells.…”

Section: Introductionmentioning

confidence: 99%

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

et al. 2008

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T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-g (IFN-g). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating À451 to À347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-g/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.

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“…IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g.…”

mentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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Distinct Effects of T-bet in T _H 1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells

Cited by 1,061 publications

References 28 publications

Control of Leishmania major in the absence of Tyk2 kinase

Control of Leishmania major in the absence of Tyk2 kinase

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

Persistence of effector memory Th1 cells is regulated by Hopx

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Distinct Effects of T-bet in T H 1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells

Cited by 1,061 publications

References 28 publications

Control of Leishmania major in the absence of Tyk2 kinase

Control of Leishmania major in the absence of Tyk2 kinase

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

Persistence of effector memory Th1 cells is regulated by Hopx

Contact Info

Product

Resources

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Distinct Effects of T-bet in T _H 1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells