TGF-β1 Inhibits T-bet Induction by IFN-γ in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1

Park, Il Kyoo; Shultz, Leonard D.; Letterio, John J.; Gorham, James D.

doi:10.4049/jimmunol.175.9.5666

Cited by 85 publications

(65 citation statements)

References 41 publications

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“…TGF-␤1 inhibits Th1 differentiation through the inhibition of the expression of the transcription factor T-bet (41,42), the expression of which is both necessary and sufficient for Th1 development (43). We have shown recently that TGF-␤1 requires the protein tyrosine phosphatase Shp-1 to inhibit IFN-␥-mediated up-regulation of T-bet expression (44). TGF-␤1 is capable of recruiting CD4 ϩ CD25 Ϫ T cells to the Treg effector pool, via SMAD3-mediated up-regulation of the key Treg transcription factor FoxP3.…”

Section: Tgf-␤1 Regulates Ag-specific Peripheral Cd4 ϩ T Cell Responsesmentioning

confidence: 99%

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

Robinson

Gorham

2007

The Journal of Immunology

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T cell expansion typically is due to cognate interactions with specific Ag, although T cells can be experimentally activated through bystander mechanisms not involving specific Ag. TGF-β1 knockout mice exhibit a striking expansion of CD4+ T cells in the liver by 11 days of age, accompanied by CD4+ T cell-dependent necroinflammatory liver disease. To examine whether hepatic CD4+ T cell expansion in TGF-β1−/− mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR Vβ repertoires in peripheral CD4+ T cells. We reasoned that Ag-nonspecific T cell responses would yield spectratype profiles similar to those derived from control polyclonal T cell populations, whereas Ag-specific T cell responses would yield perturbed spectratype profiles. Spleen and liver CD4+ T cells from 11-day-old TGF-β1−/− mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR Vβ CDR3 lengths, indicative of Ag-driven T cell responses. We quantitatively assessed spectratype perturbation to derive a spectratype complexity score. Spectratype complexity scores were considerably higher for TGF-β1−/− CD4+ T cells than for TGF-β1+/− CD4+ T cells. TCR repertoire perturbations were apparent as early as postnatal day 3 and preceded both hepatic T cell expansion and liver damage. By contrast, TGF-β1−/− CD4+ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4+ T cells in TGF-β1−/− mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-β1 in the peripheral regulation of Ag-specific CD4+ T cell responses.

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Section: Tgf-␤1 Regulates Ag-specific Peripheral Cd4 ϩ T Cell Responsesmentioning

confidence: 99%

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

Robinson

Gorham

2007

The Journal of Immunology

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“…TGFβ1 inhibits Ifng expression through the inhibition of Tbx21 and Stat4, which are known to induce T h 1-cell differentiation [12,28]. The inhibitory effect of TGFβ1 on Tbx21 expression is mediated through Src homology region 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) [29], a negative regulator of T-cell receptor (TCR) signaling and T reg -cell generation. TGFβ1 also inhibits T h 2-cell differentiation by inhibiting Gata3 expression in mouse but not human T cells [30,31].…”

Section: Tgfβ1 Signaling In T Cellsmentioning

confidence: 99%

TGFβ1 and Treg cells: alliance for tolerance

Bommireddy

Doetschman

2007

Trends in Molecular Medicine

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Transforming growth factor β1 (TGFβ1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T reg )-cell and effector-cell function and tumorigenesis. Defects in TGFβ1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFβ1 prevents abnormal T-cell activation through the modulation of Ca 2+ -calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T reg cells, its effects are mediated, at least in part, through SMAD signaling. TGFβ1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T h IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFβ1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

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“…SHIP has previously been shown to regulate TGF␤ function in macrophages (18). Moreover, the tyrosine phosphatase SHP-1, which inhibits signaling pathways triggered by the same immune receptors as SHIP, is essential for the TGF␤ inhibition of IFN␥ induction of T-bet expression (28). Freshly isolated CD4cre SHIP fl/fl and control CD4 ϩ T cells were stimulated with a combination of anti-CD3 and anti-CD28 and with IFN␥ and TGF␤ separately and in combination.…”

Section: Mice With T-specific Deletion Of Ship Show Altered Response mentioning

confidence: 99%

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Тарасенко

Kole

Anthony

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The 5 -phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8 ؉ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity.cytotoxicity ͉ T-bet T he 5Ј-inositol phosphatase SHIP is a well characterized inhibitory molecule that regulates cell responses in lymphocytes and myeloid cells by its ability to hydrolyze the second messenger PI(3,4,5) trisphosphate (1-4). SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2, 9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10-13). This inhibitory effect ultimately leads to reduced calcium influx and prevents cellular activation (14).Germ-line deletion of SHIP in mice leads to early mortality from a myeloproliferative-like syndrome characterized by profound splenomegaly and massive myeloid infiltration of the lung (15). B cells develop abnormally in SHIP-null mice, with an activated phenotype and specifically lacking the marginal zone B cell population (16,17). The absence of marginal-zone B cells in SHIP-null mice has been explained not as a B cell primary defect, but as a consequence of macrophage dysregulation in the spleen of these animals (17). Macrophages from SHIP-null mice are skewed toward an M2-activated phenotype showing high levels of arginase I (ArgI) and Ym1. R...

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TGF-β1 Inhibits T-bet Induction by IFN-γ in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1

Cited by 85 publications

References 41 publications

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

TGFβ1 and Treg cells: alliance for tolerance

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

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