Signal transduction and Th17 cell differentiation

John J. O’Shea,a Scott M. Steward-Tharp,ab* Arian Laurence,a Wendy T. Watford,a Lai Wei,a Adewole S. Adamson,ac and Samuel Fanad

a Molecular Immunology and Inflammation Branch, National Institutes of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892

b Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814
c Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, MA 02115
d Department of Biology, Bradley University, Peoria, IL 61625
*Corresponding author. Telephone: 301-402-4886. Fax: 301-480-6372. Email: Mailing Address: 10 Center Dr RM 13C103 Bethesda, MD, 20892-1930


The paradigm of effector T helper cell differentiation into either Th1 or Th2 lineages has been notably shaken by the discovery of a third lineage of cells that selectively produce interleukin (IL)-17. Characterization of this new subset, referred to as Th17, has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Additionally, the discovery of this T cell subset has offered a fresh look at such concepts as lineage commitment and terminal differentiation. The transcriptional regulatory events and epigenetic modifications that control these processes are diverse and complex, and despite the rapid pace at which data continues to accumulate, many questions remain to be answered. Here we review our current understanding of the signaling pathways, molecular interactions and transcriptional events that lead to Th17 differentiation and effector function, as well as the epigenetic modifications that accompany them.

Keywords: Th17, IL-17, Signal transduction, Transcription factor, Lymphocyte differentiation, Cytokines, Chromatin


Successful host defense relies on communication between cells of the innate and adaptive immune system. The seminal studies initiated by Coffman and Mossman and expanded by many others, provided the first clues of how helper T cells orchestrate proper innate and adaptive responses to microbial pathogens [13]. These studies also provided considerable insight into our understanding of T cell activation and the selective regulation of gene expression, providing robust models for understanding mechanisms of gene regulation and T cell fate determination [2, 4, 5] [6]. Despite its utility, a simple, static Th1/Th2 view of T cell differentiation implies rather inflexible responses, but recent discoveries have emphasized that T cells are anything but static in their responses.

We now appreciate that IL-17-producing helper T cells or Th17 cells represent another subset of CD4+ T cells. These cells have critical roles in host defense against extracellular bacteria and also play pivotal roles in the pathogenesis of autoimmune disease. Th17 cells produce a range of cytokines including TNF, IL-17A, IL-17F, IL-21 and IL-22, but a simplistic view of these cells as merely another “lineage” of T cells unravels somewhat when one considers a number of points. First, it is apparent in vitro and in vivo that some T cells can produce both IFN-γ and IL-17; exactly where these cells fit in the spectrum of Th17 and Th1 cells is unclear. In humans, IL-17/IFN-γ double producers and IL-17 single producers can be distinguished by their chemokine receptor expression [7]. Second, although IL-21 and IL-22 are produced by Th17 cells, they can also be produced in the absence of IL-17 [810]. Third, we now recognize that Th17 cells, as well as other T cell subsets produce IL-10; as a result, not all Th17 cells are “pathogenic” [11]. Finally, there is evidence that another critical subset of CD4+ T cells, regulatory T (Treg) cells, is related to Th17 cells [12]. Treg cells are CD4+ CD25+ cells found in the thymus and in the periphery, which express the forkhead box protein transcription factor, Foxp3. We now know that some of the factors that contribute to the differentiation of Tregs also drive Th17 differentiation, and there is evidence indicating that Treg cells can become pathogenic Th17 cells. Additionally, there are data indicating that Th17 cells can express Foxp3 and that the respective Th17 and Treg lineage “master regulators” interact.

In this review, we will discuss the receptors and signaling pathways that promote the differentiation of Th17 cells, bearing in mind that the concept of a Th17 cell may be a moving target. Th17 cells are capable of producing a range of cytokines and may not always constitute a stable “lineage”. Consequently, understanding the regulation of IL-17 is not synonymous with “lineage commitment” or terminal differentiation of Th17 cells – if indeed, this concept is appropriate.

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Signal transduction and Th17 cell differentiation