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Control of Type 1 Autoimmune Diabetes by Naturally Occurring CD4 + CD25 + Regulatory T Lymphocytes in Neonatal NOD Mice
Author(s) -
PICCIRILLO C. A.,
TRITT M.,
SGOUROUDIS E.,
ALBANESE A.,
PYZIK M.,
HAY V.
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1361.048
Subject(s) - il 2 receptor , nod mice , nod , interleukin 21 , biology , t cell , pancreatic islets , cytokine , regulatory t cell , immune system , autoimmunity , immunology , islet , endocrinology , insulin , diabetes mellitus
A bstract : 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.