There is increasing evidence that the immune response can be inhibited by several T cell subsets, including NK T cells, CD25+CD4+ T cells, and a subpopulation of CD8+ T cells. Animal model studies of multiple sclerosis have suggested an important role for suppressor CD8+ T cells in protection against disease recurrence and exacerbation. The molecular lynchpin of CD8+ suppressive activity is the murine MHC molecule Qa-1, termed HLA-E in humans. Here we summarize findings from work on Qa-1 that have begun to delineate suppressor CD8+ T cells and their mechanisms of action in the context of self tolerance and autoimmune disease.