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While intrathymic MHC expression influences the specificity of developing thymocytes, we considered that peripheral MHC expression might influence the reactivity of postthymic T cells. We now report for CD4+ T cells that peripheral MHC-II expression does influence their reactivity and self-tolerance. Upon transfer into MHC-II-deficient lymphopenic hosts, mature CD4+ T cells were found to acquire an activated memory phenotype and to become: (1) autoreactive against syngeneic MHC-II+ skin grafts, (2) hyperreactive against third-party MHC-II+ skin grafts, and (3) functionally dysregulated, resulting in a lymphoproliferative disorder characterized by intraepithelial infiltrations. Peripheral MHC-II expression appeared to influence CD4+ T cell reactivity by two complementary mechanisms: maintenance of CD4+CD25+ regulatory T cells (“suppression”) and direct dampening of CD4+ T cell reactivity (“tuning”).