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

Abstract

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.

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

“…In contrast, the Th1 transcription factor T-bet was expressed in the Eomes + population (Fig. 3C), which is in line with published data (22,40). Consistent with the transcription factor expression, Eomes + cells produced IFN-g, but no IL-17A (Fig.…”

“…This might be partly due to low levels of Eomes expression under steady state conditions (19). A previous report identified Eomes expression in a small population of nonconventional intestinal intraepithelial Th1 CD4 + T lymphocytes with an activated phenotype (40). Eomes was also shown to be expressed by a subset of memory T lymphocytes generated after adoptive transfer of Th2 cells into a nude host (10).…”

“…Previous reports indicated a role of Eomes in the control of effector proinflammatory Th subsets. Gain-and loss-of-function experiments in both CD8 + (14,21,38,59) and CD4 + (8,11,22,40) T cells have shown that Eomes promotes cytotoxicity and IFN-g production in mice and humans. 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).…”

THE ROLE OF THE DIFFERENT SUBPOPULATIONS OF CD4⁺Т LYMPHOCYTES DURING PREGNANCY

“…TGF-β inhibits IFNγ-mediated differentiation, proliferation, and secretion of cytokines by Th1 cells [40,86,121]. Recently, an alternative method of Th1 differentiation, constituting an action of cytokine IL-4, TGF-β, and IFNγ totality on naive T lymphocytes, has been described [126]. Th1 lymphocytes, obtained in such a way, are distinguished by an expression of CD103, thus, the authors do separate them into CD103 + Th1 cell subpopulation.…”

Differentiation, Regulation and Function of Th9 Cells

“…A recent report indicates that naïve CD4 + T cells cultured with a combination of IL-4, TGF-β, and IFN-γ tend to acquire the phenotype of Th1 cells other than Th9 cells. The co-expression IFN-γ and surface marker CD103 depend on T-bet and STAT6 signaling induced Eomesodermin [77].…”