Control of Type 1 Autoimmune Diabetes by Naturally Occurring CD4+CD25+ Regulatory T Lymphocytes in Neonatal NOD Mice

Authors


Address for correspondence: Dr. Ciriaco A. Piccirillo, Departments of Microbiology and Immunology & Center for the Study of Host Resistance, McGill University, 3775 University Street, Room 408, Lyman Duff Medical Building, Montreal, QC, Canada, H3A 2B4. Voice: 514-398-2872; fax: 514-398-7052. Ciro.piccirillo@mcgill.ca

Abstract

Abstract: Nonobese diabetic (NOD) mice serve as a model of spontaneous type 1 diabetes (T1D), a T cell-mediated autoimmune disease leading to the destruction of pancreatic insulin-producing beta islet cells. A possible deficiency in regulatory T (Treg) cell development or function may promote the activation, expansion, and recruitment of autoreactive T cells and the onset of T1D. Naturally occurring CD4+CD25+ Treg (nTreg) cells, which typically display potent inhibitory effects on T cell functions in vitro and in vivo, may be defective at controlling autoimmunity in T1D. We have examined the relative contribution of CD4+CD25+ nTreg cells in the immune regulation of T1D in the NOD mouse model. CD4+CD25+ T cells represent 5-10% of CD4+ thymocytes or peripheral T cells from prediabetic neonatal NOD mice, are anergic to TCR signals, and potently suppress activated T cells in a contact-dependent and cytokine-independent fashion in vitro. Unlike total CD4+ T cells, prediabetic CD25+-depleted CD4+ T cells are potently diabetogenic when transferred in immunodeficient NOD mice. Co-transfer of CD4+CD25+ T cells from thymocytes or peripheral lymphoid tissues of neonatal NOD mice dramatically halts disease development and beta-islet cell lymphocytic infiltration, even when T1D is induced by CD4+ T cells from BDC2.5 transgenic or diabetic NOD mice. Finally, we show that CD4+CD25+ Treg preferentially accumulate in inflamed pancreatic environments, where they potently inhibit the antigen-specific expansion and cytokine effector functions of diabetogenic T cells. Thus, CD4+CD25+ T cell-mediated regulation is operative in the prediabetic neonatal T cell repertoire and can suppress the diabetogenic process and control the onset of T1D.

Ancillary