Th17 Cells: Differentiation and Regulation

Abstract

The increased IL-17A production by CD4+ T cells from T cell receptor (TCR) transgenic DO11.10 mice was first observed by Infante-Duarte and colleagues in 2000 [1]. The transgenic TCR recognizes ovalbumin (OVA) peptide 322-339 in association with I-Ad. When stimulated with OVA322-339 in the presence of cell lysates of Borrelia burgdorferi, these CD4+ Th cells preferentially produce IL-17A along with tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytokine profile produced by these CD4+ Th cells is distinctive from those by Th1 or Th2 cells. Interleukin 6 (IL-6) was shown to have a similar effect to cell lysates of Borrelia burgdorferi in inducing IL-17A production by these CD4+ Th cells. In 2003, Aggarwal et al. [2] showed that IL-23 preferentially promotes IL-17A and IL-17F production by activated CD4+ T cells in vitro suggesting that during a secondary immune response IL-23 can promote a distinct differentiation status from well-characterized Th1 and Th2 cells. In an experimental autoimmune encephalomyelitis (EAE) model, Cua and colleagues demonstrated that it is IL-23 rather than IL-12 mediating autoimmune inflammation of the brain [3]. Furthermore, they provided in vivo evidence that IL-23 drives a pathogenic T cell population mediating inflammation in EAE and arthritis models [4, 5]. These pathogenic CD4+ T cells produce IL-17A, IL-17F, IL-6, and TNF. The term “Th17 cells” was proposed in 2005 by two independent groups led by Dong and Weaver, respectively [6, 7], to describe a Th cell lineage, which is distinctive from Th1 and Th2 cells. A Th17 cell is governed by its master transcription factor, retinoic acid receptor-related orphan nuclear receptor (ROR)-γt [8]. The discovery of Th17 cells heralded a major shift in T cell biology and our understanding of the mechanism of autoimmune inflammatory diseases. Cytokines produced by Th17 cells include IL-17A, IL-17F, IL-22, GM-CSF, IL-21, and TNF depending on inflammatory settings [9]. Those autoimmune diseases thought to be mediated by Th1 cells are now recognized to be mediated mainly by Th17 cells [10].