Mice lacking the C-type lectin receptor CD69 develop exacerbated forms of arthritis, contact dermatitis, allergic asthma, and autoimmune myocarditis. Because the immune responses in these diseases are largely mediated by a balance between proinflammatory subsets of T effector cells called T helper (T_H) 17 cells and regulatory T cells, these findings indicate a previously unappreciated regulatory role for CD69 in modulating T lymphocyte differentiation toward the T_H17 lineage and suggest a role in regulatory T cell function. CD69 promotes activation of the Jak3−signal transducer and activator of transcription 5 (Stat5) signaling pathway, which inhibits T_H17 cell differentiation, thus providing a mechanistic link between CD69 and the regulation of T_H17 responses. This evidence underscores the potential of CD69 as target in the treatment of autoimmune and allergic diseases and is consistent with mounting evidence linking CD69 to regulatory T cell subsets.