The mouse protein Qa-1 (HLA-E in humans) is essential for immunological protection and immune regulation. Although Qa-1 has been linked to CD8 T cell–dependent suppression, the physiological relevance of this observation is unclear. We generated mice deficient in Qa-1 to develop an understanding of this process. Qa-1-deficient mice develop exaggerated secondary CD4 responses to foreign and self peptides. Enhanced responses to proteolipid protein self peptide were associated with resistance of Qa-1-deficient CD4 T cells to Qa-1-restricted CD8 T suppressor activity and increased susceptibility to experimental autoimmune encephalomyelitis. These findings delineate a Qa-1-dependent T cell–T cell inhibitory interaction that prevents the pathogenic expansion of autoreactive CD4 T cell populations and consequent autoimmune disease.