Thymic selection by a single MHC/peptide ligand: Autoreactive T cells are low-affinity cells

In H2-M- mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4(+) cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M- CD4(+) cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here, however, that such "self" reactivity is controlled by low-affinity CD4(+) cells. These cells give spectacularly high proliferative responses but are virtually unreactive in certain other assays, e.g., skin graft rejection; responses to MHC alloantigens, by contrast, are intense in all assays. Possible explanations for why thymic selection directed to a single peptide curtails self specificity without affecting alloreactivity are discussed.