Trends in Immunology
ReviewDefining the human T helper 17 cell phenotype
Section snippets
Beyond the Th cell Th1/Th2 paradigm
Activated CD4+ Th cells can be subdivided into lineages based on their cytokine secretion, transcription factor expression, and immunological function. Initially, CD4+ Th cells were thought of as having one of two possible fates: Th1 or Th2 cells. Th1 cells express the transcription factor T-bet, secrete interferon (IFN)-γ and protect the host against intracellular infections. Th2 cells express GATA binding protein 3 (GATA-3), secrete IL-4, IL-5 and IL-13, and mediate host defense against
Cytokines and chemokines produced by Th17 cells
Both murine and human Th17 cells produce IL-17A and IL-17F, and these cytokines have been used to define this subset 3, 4, 5. IL-17A and IL-17F are similar in their biological activity, target both immune and nonimmune cell types (Figure 1), and play an important role in the inflammatory response. IL-17A induces chemokine CXC ligand (CXCL)8 production from epithelial cells, endothelial cells, fibroblasts and macrophages, leading to recruitment of neutrophils. In addition, several cell types in
Th17 cell transcription factors
Murine Th17 cells express the transcription factor retinoic acid orphan receptor (ROR)γt (Rorc), but not T-bet or GATA-3 25, 26. RORγt is a master regulator of Th17 cell differentiation, and Rorc deletion dramatically reduces the number of Th17 cells in mutant mice as a result of impaired Th17 cell differentiation [25]. Murine Th17 cells also express Rora. Deletion of Rora alone has little effect on IL-17 production, however, deficiency of both Rora and Rorc completely abolishes Th17
Human Th17 cell cytokine and chemokine receptors
Murine Th17 cells express several cytokine receptors, most of which were identified based on the ability of the corresponding cytokine to induce Th17 cell differentiation. These include the IL-6 receptor (IL-6R), transforming growth factor (TGF)-β receptor, IL-23R, IL-21R, and IL-1R. Differentiation of naïve murine Th cells into Th17 cells was initially suggested to result from the combined activity of IL-6 and TGF-β in vitro 36, 37, 38. IL-23 induces expansion and/or maintain survival of Th17
Markers associated specifically with human Th17 cells
The factors characteristic of the Th17 cell phenotype discussed so far are relevant for both human and mouse Th17 cells. Recent work has identified expression of CD161 and IL4I1 specifically in human Th17 cells.
Concluding remarks
Several features of murine Th17 that were described early on have since been challenged by human studies, and also in more recent work on mouse Th17 cells. For example, the requirement for TGF-β for in vitro development of Th17 cells is now controversial. It is also emerging that Th17 cells are plastic, with the ability to shift to Th1-like cells at inflamed sites. Expression of the IL-12Rβ2 chain on the cell surface contributes to Th17 cell plasticity 16, 51, which allows Th17 cells to
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