The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-γ negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-Producing T cells

A novel transcription factor, T-bet, directs Th1 lineage commitment.

The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells

T helper 1 (TH1) cells mediate cellular immunity, whereas TH2 cells potentiate antiparasite and humoral immunity We used a complementary DNA subtraction method, representational display analysis, to show that the small guanosine triphosphatase Rac2 is expressed selectively in murine TH1 cells Rac induces the interferon-γ (IFN-γ) promoter through cooperative activation of the nuclear factor kappa B and p38 mitogen-activated protein kinase pathways Tetracycline-regulated transgenic mice expressing constitutively active Rac2 in T cells exhibited enhanced IFN-γ production Dominant-negative Rac inhibited IFN-γ production in murine T cells Moreover, T cells from Rac2−/− mice showed decreased IFN-γ production under TH1 conditions in vitro Thus, Rac2 activates TH1-specific signaling and IFN-γ gene expression

https://science.sciencemag.org/content/sci/288/5474/2219.full.pdf

Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation.

Differentiation of Th cells from naive precursors is a dynamic process that involves multiple transcription factors acting at specific time points to regulate gene expression. In this study we show that the homeobox transcription factor Hlx is up-regulated early in Th1 cell differentiation. Mice constitutively expressing an Hlx transgene driven by a CD4 promoter showed marked reduction in the CD4 + CD8 + thymocyte population. The Hlx transgenic mice generated increased numbers of Th1 cells in response to keyhole limpet hemocyanin immunization. After differentiation under Th2-polarizing conditions in vitro, the transgenic CD4 T cells expressed high levels of IFN-γ. Intracellular cytokine staining revealed that in addition to Th2 cells, large numbers of Th0 and Th1 cells were generated from such in vitro differentiated transgenic CD4 T cells. Retrovirally overexpressed Hlx also induced the aberrant expression of IFN-γ in normal CD4 T cells differentiated under Th2-polarizing conditions. This effect was apparent only when Hlx was introduced into the cells by retroviral infection at an early time point that led to the expression of the retrovirally transferred Hlx gene at a time comparable to that of the up-regulation of the endogenous Hlx during Th1 cell differentiation. Later infection with Hlx-expressing retrovirus showed no effect. Thus, the induction of IFN-γ expression by Hlx depends on a permissive epigenetic state of the IFN-γ gene locus and/or the molecular context of the immature Th cells.

Wei-ping Zheng

Papers

The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells

Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation.

Up-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression

Pillars Article: The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells. Cell. 1997. 89: 587-596.

The regulation of cd4 t cell differentiation