Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment.
Previous results have shown that CD4(+)CD25(+) regulatory T cells (Tregs) control autoimmunity in a spontaneous model of type 1 diabetes, the nonobese diabetic (NOD) mouse. Moreover, anti-CD3 reverses diabetes in this setting by promoting Tregs that function in a TGF-beta-dependent manner. This finding contrasts with a large body of work suggesting that CD4(+)CD25(high) Tregs act in a cytokine-independent manner, thus suggesting that another type of Treg is operational in this setting. We sought to determine the basis of suppression both in untreated NOD mice and in those treated with anti-CD3. Our present results show that a subset of foxP3(+) cells present within a CD4(+)CD25(low) lymphocyte subset suppresses T cell immunity in spontaneously diabetic NOD mice in a TGF-beta-dependent manner, a functional property typical of "adaptive" regulatory T cells. This distinct Treg subset is evident in NOD, but not normal, mice, suggesting that the NOD mice may generate these adaptive Tregs in an attempt to regulate ongoing autoimmunity. Importantly, in two distinct in vivo models, these TGF-beta-dependent adaptive CD4(+)CD25(low) T cells can be induced from peripheral CD4(+)CD25(-) T lymphocytes by anti-CD3 immunotherapy which correlates with the restoration of self-tolerance.
You
Sylvaine
S
Université Paris Descartes, 75015 Paris, France.
Leforban
Bertrand
B
Garcia
Corinne
C
Bach
Jean-François
JF
Bluestone
Jeffrey A
JA
Chatenoud
Lucienne
L
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007140:Immunoglobulin Fab Fragments; D016212:Transforming Growth Factor beta