Properties and origin of human Th17 cells

Abstract

Following the discovery of distinct subsets of CD4+ T-cell effectors, known as type 1 T helper (Th1) and type 2 Th (Th2), which mainly produce interferon (IFN)-gamma or interleukin (IL)-4, respectively, a novel population has been discovered and named as type 17 Th (Th17) because of the its unique ability to produce IL-17A. Murine Th17 cells play a protective role against extracellular bacteria and fungi by inducing an inflammatory response characterized not only by the presence of mononuclear cells but also of neutrophil granulocytes. Murine Th17 cells have been considered as major players in the pathogenesis of murine autoimmune disorders while Th1 cells seemed to have a protective role. However, this concept has recently been challenged by the demonstration that either Th17 or Th1 cells may be pathogenic even in murine models of autoimmune disorders. Th17 cells have also been identified in human blood and inflamed tissues, but they seem to exhibit different features from murine Th17 cells. First, human Th17 are characterized by the surface expression of CCR6 and IL-23R, but also of IL-12Rbeta2 and CD161. Second, human Th17 cells express T-bet in addition to retinoic acid-related orphan receptor (ROR)gammat and can be induced to produce IFN-gamma in addition to IL-17A in the presence of IL-12, thus suggesting a close developmental relationship with Th1 cells. Finally, while murine Th17 originate from a precursor common to Foxp3+ T regulatory (Treg) cells when IL-6 is produced in combination with TGF-beta, human Th17 cells originate from CD161+CD4+ precursors, which constitutively express RORgammat and IL-23R, in response to the combined activity of IL-1beta and IL-23. By contrast, TGF-beta does not play a direct role in human Th17 differentiation, but can only favour their expansion by inhibiting T-bet expression and the development of Th1 cells.