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

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 (T(reg)) cell development or function may promote the activation, expansion, and recruitment of autoreactive T cells and the onset of T1D. Naturally occurring CD4(+)CD25(+) T(reg) (nT(reg)) 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(+) nT(reg) 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(+) T(reg) 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.

A cis-Acting Regulatory Variant in the IL2RA Locus

“…CD4 ϩ CD25 ϩ T cells, naturally generated in the thymus, is a population of regulatory T cells that plays an important role in maintaining immune homeostasis and inhibiting autoimmune disease by suppressing activated T cells (18). The crucial role of CD4 ϩ CD25 ϩ T cells in a T1D mouse model has been suggested by multiple studies and reviewed by Piccirillo et al (19) IL-2 is an absolute requirement for the expansion of CD4 ϩ CD25 ϩ T cells in NOD mice and has been suggested as a potential therapeutic agent in the prevention of T1D (20). Currently, the IL-2 treatment for T1D is being tested in a clinical trial (Identifier no.…”

Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation

“…limiting autoimmune tissue damage has also been documented in disease models for multiple sclerosis 4 , type I diabetes 5,6 and rheumatoid arthritis 7 . In humans, a decreased frequency of occurrence of T-reg 8 or defects in their suppressor function 9 have been demonstrated in multiple sclerosis and lupus 10,11 .…”

Genome-Wide DNA Methylation Profiling in Diabetogenic and Regulatory T Cells from NOD Mice

“…+ CD4 + regulatory T cells (Tregs) and antigen-expanded Foxp3 -CD4 + Tregs are important for maintaining immune tolerance and preventing autoimmune diseases, by suppressing pathogenic T cells (Tpaths) [21][22][23][24][25][26][27][28]. These studies suggest that an increased population of autoreactive Tpaths, the presence of Tregs-resistant Tpaths, or a defective population of Tregs may lead to development of diabetes.…”