On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

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

CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...

IL-17 and Th17 Cells.

Regulatory T Cells and Immune Tolerance

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

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Differentiation of Effector CD4 T Cell Populations

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25− naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-β induced Foxp3 gene expression in TCR-challenged CD4+CD25− naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-β and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-β–converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-β–induced suppressor T cells prevented house dust mite–induced allergic pathogenesis in lungs.

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Li Li

Papers

Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3