The C-type lectin-like receptor CD161, which has recently been described to promote T cell expansion, is expressed on a discrete subset of human CD4 T cells. The function of such cells, however, has remained elusive. We now demonstrate that CD161 + CD4 T cells comprise a circulating and gut-resident T helper 17 (Th17) cell population. During Crohn ' s disease (CD), these CD161 + cells display an activated Th17 phenotype, as indicated by increased expression of interleukin (IL)-17, IL-22, and IL-23 receptor. CD161 + CD4 T cells from CD patients readily produce IL-17 and interferon γ upon stimulation with IL-23, whereas, in healthy subjects, priming by additional inflammatory stimuli such as IL-1β was required to enable IL-23-induced cytokine release. Circulating CD161 + Th17 cells are imprinted for gut homing, as indicated by high levels of CC chemokine receptor 6 and integrin |β7 expression. Supporting their colitogenic phenotype, CD161 + Th17 cells were found in increased numbers in the inflammatory infiltrate of CD lesions and induced expression of inflammatory mediators by intestinal cells. Our data identify CD161 + CD4 T cells as a resting Th17 pool that can be activated by IL-23 and mediate destructive tissue inflammation.
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