The ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1–Qdm on activated T cells responsible for adaptive immunity and CD94–NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1–Qdm binding to CD94–NKG2A receptors. The Qa-1–NKG2A interaction protected activated CD4⁺ T cells from lysis by a subset of NKG2A⁺ NK cells and was essential for T cell expansion and development of immunologic memory. Antibody-dependent blockade of this Qa-1–NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings extend the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of antigen-activated T cells in the context of autoimmune disease and transplantation.