The Transcription Factor GATA3 Actively Represses RUNX3 Protein-Regulated Production of Interferon-γ

Cytokine storm has been postulated as one of the major causes of mortality in patients with severe respiratory viral infections such as influenza. With the help of an influenza Ag- specific mouse experimental system, we report that CD4+ T cells contribute effector cytokines leading to lung inflammation in acute influenza. Although virus can no longer be detected from tissues 14 d postinfection, virus-derived Ag continues to drive a CD4+ T cell response after viral clearance. Ag-specific CD4+ T cells proliferate and evolve into memory CD4+ T cells efficiently, but the production of effector cytokines is seriously hampered during this phase. This decoupling of proliferation and effector cytokine production doesn’t appear in conjunction with increased suppression by regulatory T cells or decreased induction of transcription factors. Rather, GATA-3 and ROR-γt levels are elevated when compared with cells that have effector cytokine production. T-bet dominance over GATA-3 and ROR-γt decreases with the disarmament of effector cytokine production. Importantly, upon reinfection, these decoupled cells produce elevated levels of IFN-γ and were effective in virus eradication. These results provide a mechanism through altered T-bet dominance to dampen the cytokine storm without impeding the generation of memory T cells in influenza virus infection.

Section: Discussionmentioning

confidence: 91%

Altered T-bet Dominance in IFN-γ–Decoupled CD4+ T Cells with Attenuated Cytokine Storm and Preserved Memory in Influenza

Dutta

Miaw

et al. 2013

“…However, none of these settings showed essential functions of Eomes for the induction of IFN-g, probably due to compensatory effects of the related transcription factor Tbet (21,22,57). Indeed, Eomes can be expressed by T-bet-deficient T cells and partially replace T-bet function (8,23,24,57). Although T-bet is not required for Eomes expression, it can enhance it by preventing the expression of known inhibitors of Eomes such as GATA3 (9,23,60).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, Eomes can be expressed by T-bet-deficient T cells and partially replace T-bet function (8,23,24,57). Although T-bet is not required for Eomes expression, it can enhance it by preventing the expression of known inhibitors of Eomes such as GATA3 (9,23,60). According to redundant functions between Eomes and T-bet, we did not observe differences in the accumulation of Eomes-deficient Th1 cells under inflammatory conditions or under steady state, despite the fact that the majority of Eomes + WT cells under those conditions were active producers of IFN-g.…”

Section: Discussionmentioning

confidence: 99%

“…However, T-bet-deficient CD4 + T cells can still produce some IFN-g, which is thought to rely on Eomes functions (8,9,(22)(23)(24). In line with its effects on CD8 + T cells, Eomes overexpression in CD4 + T cells also promotes IFN-g production (8,9,14,22,23) and cytotoxicity (11). In contrast, different experimental studies suggest that, like T-bet, Eomes is able to actively suppress the development or function of non-Th1 CD4 + subsets.…”

Section: T He Cd4 + T Cells Coordinate Different Types Of Immunementioning

confidence: 99%

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Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

“…Yagi et al (39) reported high levels of Eomes and IFN-g secretion in Gata3-deficient CD4 T cells cultured under Th2 conditions. They concluded that Gata3 blocks the Runx3-Eomes-IFN-g pathway, presumably through interaction with Runx3.…”

Section: Discussionmentioning

confidence: 99%

Identification of a New Pathway for Th1 Cell Development Induced by Cooperative Stimulation with IL-4 and TGF-β

Tofukuji

Kuwahara

Suzuki

et al. 2012

IL-4 plays an important role in the induction of Th2 and Th9 cells, as well as in the inhibition of Th1 cell generation. We show that a combination of IL-4 and TGF-β augments the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFN-γ is present. The T-box–containing transcription factor eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells and is involved in IFN-γ production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFN-γ gene loci. TGF-β is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6-signaling pathway. IFN-γ–producing CD103+ Th1 cells are detected in the intraepithelial lymphocytes of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. To our knowledge, these results represent the first molecular mechanism of IL-4/TGF-β–dependent augmentation of Th1 cell generation and raise the possibility that IL-4 and TGF-β simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions.