In mice, Ag administration in the absence of adjuvant typically elicits tolerogenic immune responses through the deletion or inactivation of conventional CD4 T cells and the formation or expansion of regulatory CD4 T cells (Treg). Although these "Ag-specific immunotherapy" (ASI) approaches are currently under clinical development to treat autoinflammatory conditions, efficacy and safety may be variable and unpredictable because of the diverse activation states of immune cells in subjects with autoimmune and allergic diseases. To reliably induce Ag-specific tolerance in patients, novel methods to control T cell responses during ASI are needed, and strategies that permanently increase Treg frequencies among Ag-specific CD4 T cells may provide long-lasting immunosuppression between treatments. In this study, we present an approach to durably increase the frequency of Ag-specific Treg in mice by administering ASI when Treg numbers are transiently increased with individual doses of a half-life-extended Treg-selective IL-2 mutein. Repeated weekly cycles of IL-2 mutein doses (day 0) followed by ASI (day 3) resulted in a 3- to 5-fold enrichment in Treg among Ag-responsive CD4 T cells. Expanded Ag-specific Treg persisted for more than 3 wk following treatment cessation, as well as through an inflammatory T cell response to an Ag-expressing virus. Combining Treg enrichment with ASI has the potential to durably treat autoimmune disease or allergy by increasing the Treg/conventional CD4 T cell ratio among autoantigen- or allergen-specific T cells.
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