Growing evidence indicates that collagen-binding integrins are important costimulatory molecules of effector T cells. In this study, we demonstrate that the major collagen-binding integrin expressed by human Th17 cells is alpha2beta1 (α2β1) or VLA-2, also known as the receptor for collagen I on T cells. Our results show that human naïve CD4(+) T cells cultured under Th17 polarization conditions preferentially upregulate α2β1 integrin rather than α1β1 integrin, which is the receptor for collagen IV on T cells. Double staining analysis for integrin receptors and intracellular IL-17 showed that α2 integrin but not α1 integrin is associated with Th17 cells. Cell adhesion experiments demonstrated that Th17 cells attach to collagen I and collagen II using α2β1 integrin but did not attach to collagen IV. Functional studies revealed that collagens I and II but not collagen IV costimulate the production of IL-17A, IL-17F and IFN-γ by human Th17 cells activated with anti-CD3. These results identify α2β1 integrin as the major collagen receptor expressed on human Th17 cells and suggest that it can be an important costimulatory molecule of Th17 cell responses. <<<