Qa-1 restriction of CD8+ suppressor T cells

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. Mechanisms of peripheral toleranceThe first stages of T cell development occur in the thymus, where a selection process weeds out potentially autoreactive cells.Successful progression of thymocytes through selection requires expression of TCRs capable of efficient binding to self-MHC products.Although T cell clones bearing TCRs with high affinity for selfpeptide MHC products are generally eliminated during this process, the resulting T cell repertoire is still strongly biased toward self reactivity (1).As a result, substantial numbers of peripheral T cells can proliferate in response to self-peptide MHC complexes, and some can differentiate into effector cells in the context of inflammatory stimuli (2-4).Expansion of autoreactive T cells in peripheral lymphoid tissues is constrained, in part, by abortive TCR signals that lead to T cell elimination or inactivation (5,6).However, mechanisms of T cell elimination that include activation-induced cell death (AICD) and anergy, an insensitivity to antigens that creates an inability to elicit a normal antigenic response, may not suffice to prevent autoimmune disease (7,8).The apparent limitations of these mechanisms for eliminating all self-reactive cells have stimulated research into T cells and other cell types, so-called suppressor T cells, that may exert dominant inhibitory effects on expansion of pathogenic autoreactive T cells.One such group of cells is the suppressor CD8 + T cells. Suppressor CD8 + T cells and Qa-1The recent resurgence of interest in suppressor T cells has been largely due to the delineation of a CD4 + sublineage with regulatory activity (9-13).The possibility that CD8 + T cells might also contain a regulatory sublineage has received much less attention despite the fact that CD8 + T cells were the initial target of work in this area.Early research used experimental systems that mainly measured in vitro antibody responses to complex antigens such as foreign erythrocytes as well as in vivo contact hypersensitivity and delayed-typehypersensitivity reactions.Downregulation of these responses by subpopulations of CD8 + T cells was then difficult to distinguish from modes of inhibition that were not yet well understood, includ-