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TH17 cells in development: an updated view of their molecular identity and genetic programming

Nature Reviews Immunology volume 8, pages 337–348 (2008)Cite this article

Key Points

  • T helper 17 (TH17) cells are a newly described subset of effector T cells.

  • TH17 cells produce interleukin-17 (IL-17), IL-17F, IL-21 and IL-22.

  • TH17-cell differentiation is initiated by transforming growth factor-β (TGFβ) and IL-6; differentiation is sustained by IL-21 and possibly completed or maintained by IL-23.

  • TH17-cell-specific genetic programming is mediated by signal transducer and activator of transcription 3 (STAT3), downstream of IL-6 and IL-21.

  • TH17 cells express two orphan nuclear receptors, retinoic-acid-receptor-related orphan receptor-α (RORα) and RORγ, which are required for TH17-cell differentiation.

Abstract

Following activation, CD4+ T cells differentiate into different lineages of helper T (TH) cells that are characterized by distinct developmental regulation and biological functions. TH17 cells have recently been identified as a new lineage of effector TH cells, and they have been shown to be important in immune responses to infectious agents, as well as in various immune diseases. Over the past two to three years, there has been a rapid progress in our understanding of the differentiation programme of TH17 cells. Here, I summarize our current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of TH17 cells, and provide my personal perspectives on the future studies that are required to elucidate this lineage in more detail.

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Figure 1: General scheme of T-helper-cell differentiation.
Figure 2: Cytokine-mediated regulation of TH17-cell differentiation.
Figure 3: Transcriptional regulation of TH17-cell differentiation.

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Acknowledgements

I thank my past and current colleagues in my group and our many collaborators for their scientific contributions to the knowledge described in this Review. My research is funded by the National Institutes of Health (USA), the University of Texas MD Anderson Cancer Center, the Cancer Research Institute and the American Lung Association.

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  1. Department of Immunology, MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Chen Dong

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Glossary

T helper 3 (TH3) cells

A regulatory T-cell subset that was originally thought to be involved in oral tolerance and that mainly secretes TGFβ. TGFβ produced by TH3 cells provides help for IgA class switching and has suppressive effects on both TH1 and TH2 cells. As the expression of CD25 and FOXP3 is induced in T cells under experimental TH3-cell differentiation conditions (T-cell receptor stimulation in the presence of IL-4, IL-10 and TGFβ), TH3 cells should be referred to as inducible regulatory T cells that proliferate in the periphery.

T regulatory type 1 (TR1) cells

A subset of CD4+ regulatory T cells that secrete high levels of IL-10 and that downregulate TH1- and TH2-cell responses in vitro and in vivo by a contact-independent mechanism(s) mediated by the secretion of soluble IL10 and TGFβ1.

Microarray analysis

A technique for measuring the transcription of genes. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of multiple sclerosis. EAE can be induced in several mammalian species by immunization with myelin-derived antigens together with adjuvant. The immunized animals develop a paralytic disease that has several pathological features in common with multiple sclerosis in humans.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, particularly in the kidney. Patients with SLE generally have abnormal B- and T-cell function.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B-cell follicles during an immune response. It is the main site of B-cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

Natural killer T (NKT) cell

A T cell that expresses both NK-cell receptors and an αβ-TCR. Some mouse NKT cells express an invariant TCR that uses the Vα14 variable region of the TCR α-chain and recognizes CD1d-associated antigen. NKT cells are characterized by cytolytic activity and the rapid production of cytokines, including IFNγ and IL-4, and they might regulate the function of other T cells.

γδ T cell

A T cell that expresses a T-cell receptor consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been proposed that mucosal γδ T cells are involved in innate immune responses by the mucosal immune system.

Common cytokine receptor γ-chain

(γc). A type I cytokine receptor chain that is shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

Epigenetic

This term refers to the heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin or covalent modifications of DNA and histones.

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Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8, 337–348 (2008). https://doi.org/10.1038/nri2295

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