Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes.
OBJECTIVE
In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp3(+)CD4(+) regulatory T-cells (nT(reg)), which display potent inhibitory effects on T-cell functions in vitro and in vivo, may predispose to the development of type 1 diabetes.


METHODS
We assessed the frequency and function of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues in the NOD animal model of type 1 diabetes.


RESULTS
We show that the cellular frequency of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues is stable and does not decline relative to type 1 diabetes-resistant mice. We show that thymic and peripheral CD4(+)CD25(+) T-cells are fully functional in vivo. We also examined the functional impact of CD4(+)Foxp3(+) nT(reg) cells on the development of autoimmune diabetes, and we demonstrate that nT(reg) cells do not affect the initial priming or expansion of antigen-specific diabetogenic T-cells but impact their differentiation in pancreatic lymph nodes. Moreover, CD4(+)Foxp3(+) nT(reg) cells also regulate later events of diabetogenesis by preferentially localizing in the pancreatic environment where they suppress the accumulation and function of effector T-cells. Finally, we show that the nT(reg) cell functional potency and intra-pancreatic proliferative potential declines with age, in turn augmenting diabetogenic responses and disease susceptibility.


CONCLUSIONS
This study demonstrates that Foxp3-expressing nT(reg) cells in NOD mice regulate diabetogenesis, but temporal alterations in nT(reg) cell function promote immune dysregulation and the onset of spontaneous autoimmunity.
Tritt
Michael
M
Department of Microbiology and Immunology, McGill Center for the Study of Host Resistance, McGill University, 3775 University St., Room 510, Lyman Duff Medical Building, Montreal, QC, Canada.
Sgouroudis
Evridiki
E
d'Hennezel
Eva
E
Albanese
Alexandre
A
Piccirillo
Ciriaco A
CA
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology; D007515:Islets of Langerhans; D019394:Ki-67 Antigen / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019394:Ki-67 Antigen