Production of IL-17

Abstract

et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011; 12:247-54; PMID:21278738; http://dx.doi.org/10. 1038/ni.1995 T h17 cells are important mediators of autoimmunity, yet the mechanisms by which they are controlled are not fully understood. Studies in mice, including a recent article in Nature Immunology by Yang et al., show that IL-2 is an important inhibitory factor for the differentiation of Th17 cells, inducing phosphorylation of STAT5, which out-competes STAT3 binding at the IL-17 locus. In humans however, IL-2 appears to be crucial for Th17 differentiation, yet inhibits the expansion of antigen-specific Th17 clones, again via a STAT5 mechanism. Here we discuss how the article by Yang et al. offers a novel mechanism to explain how changes in the balance of different cytokines in the inflammatory environment may alter the stability or phenotype of regulatory T cells and T helper cell subsets. It is widely accepted that T helper (Th) 1 cells and perhaps more so, Th17 cells are the key mediators of T cell pathogenesis in autoimmune disorders including multiple sclerosis, rheumatoid arthritis and colitis. When helper T cell subsets were first described, they were considered to be mutually exclusive. In the presence of IL-12, naïve T cells were shown to express STAT4 and T-bet and produce IFNc. Th2 cells could be induced in the presence of IL-4 via the upregulation of GATA-3 and STAT6. 1 Moreover, the ectopic expression of T-bet in polarized Th2 cells resulted in the production of IFNc and the suppression of Th2 cytokines. 2 Later, the discovery of Th17 cells expressing STAT3 and RORct also appeared to demonstrate a phenotype distinct from Th1 or Th2 cells. 3