The MHC class Ib molecule, CD1, has been conserved throughout mammalian evolution. To assess the function of CD1 in lymphocyte development, we generated mice with targeted disruption of the CD1.1 and CD1.2 genes. CD1-deficient mice have normal numbers of CD4(+) and CD8(+) T cells but marked reduction in NK1.1-bearing T cells, particularly those with a canonical gene rearrangement of V alpha 14-J alpha 281. CD1-deficient mice are unable to generate a rapid IL-4 response following systemic T cell activation but can generate effective antigen-specific Th2 responses. Thus, CD1 is required for the development of a specialized subset of T lymphocytes with a monomorphic antigen receptor. The rapid effector cytokine secretion of these T cells suggests that CD1 educates adaptive immune cells to subserve functions of innate immunity.