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Immunoregulatory Pathways Controlling Progression of Autoimmunity in NOD Mice
Author(s) -
You Sylvaine,
Alyanakian MarieAlexandra,
Segovia Berta,
Damotte Diane,
Bluestone Jeffrey,
Bach JeanFrançois,
Chatenoud Lucienne
Publication year - 2008
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.1447.046
Subject(s) - foxp3 , il 2 receptor , effector , autoimmunity , biology , immunology , nod , ctla 4 , microbiology and biotechnology , nod mice , transcription factor , signal transduction , immune system , t cell , in vivo , gene , genetics
The activation, expansion, and survival of regulatory T cells (Tregs) as well as the expression of their suppressive capacities result from distinct signaling pathways involving various membrane receptors and cytokines. Multiple studies have shown that thymus‐derived naturally occurring Tregs constitutively express the forkhead/winged helix transcription factor FoxP3 in addition to high levels of CD25, the negative co‐stimulatory molecule CTLA‐4, and the glucocorticoid‐induced TNF receptor‐related protein GITR. At variance, adaptive or induced Tregs acquire these phenotypic markers as they differentiate in the periphery, following adequate stimulation in the appropriate environment, together with their capacity to produce immunomodulatory cytokines (mainly, IL‐4, IL‐10 and TGF‐β) and to display regulatory capacities. However, none of these molecules but FoxP3 are restricted to Tregs since they may also be expressed and upregulated on activated effector T cells. This explains why different hypotheses were proposed to interpret interesting reports showing that in vivo abrogation of CTLA‐4 signaling using neutralizing CTLA‐4 antibodies triggers different autoimmune or immune‐mediated manifestations. Thus, an effect on pathogenic T cell effectors and/or Tregs has been proposed. Here we present and discuss recent results we obtained in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes, arguing for a key role of CTLA‐4 in the functional activity of Tregs. Moreover, data are presented that simultaneous blockade of CTLA4 and TGF‐β further impairs immunoregulatory circuits that control disease progression.