Revisiting regulatory T cells in type 1 diabetes.
OBJECTIVE
Regulatory T cells (Treg) maintain immune homeostasis and prevent autoimmune disease. This review summarizes the recent advances in Treg knowledge relevant to type 1 diabetes, focusing on Treg signature, antigen specificity and development and function in the face of inflammation.


RESULTS
Thymus-derived natural regulatory T cells (nTreg) programmed by the transcription factor forkhead box P3 (FOXP3) and peripheral-induced regulatory T cells (iTreg) have largely nonoverlapping T-cell receptor repertoires to self-antigens and jointly contribute to immune homeostasis. Initial reports that CD4CD25 (FOXP3) Treg were impaired in frequency or function in type 1 diabetes have not been confirmed. The Treg-specific demethylated region in the FOXP3 locus in nTreg is, in contrast, methylated in iTreg and conventional T cells (Tconv) and is the only feature that reliably distinguishes activated human nTreg and Tconv. Inflammatory cytokines regulate extrathymic differentiation of nTreg but can also reprogram nTreg into Th17 or Th1 effectors and prevent the differentiation of iTreg.


CONCLUSIONS
The methylation status of the FOXP3 locus provides a means to re-examine Treg in autoimmune disease. nTreg and iTreg recognize different self-antigens. Shaping of Treg by the cytokine milieu has implications for the application of Treg cell-based immune therapies.
The Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Parkville, Victoria, Australia.
Yuxia
Y
Zhang
Esther
E
Bandala-Sanchez
Leonard C
LC
Harrison
D015703:Antigens, CD / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
D015703:Antigens, CD; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors