TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes.
CD4+CD25+ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor beta (TGF-beta) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4+CD25+ T cell pool. Approximately 40-50% of intraislet CD4+ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-beta expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-beta inhibits autoimmune diseases via regulation of the size of the CD4+CD25+ regulatory T cell pool in vivo.
Peng
Yufeng
Y
Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Laouar
Yasmina
Y
Li
Ming O
MO
Green
E Allison
EA
Flavell
Richard A
RA
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003920:Diabetes Mellitus / Q000276:immunology* / Q000517:prevention & control; D004318:Doxycycline / Q000494:pharmacology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000276:immunology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
D015704:CD4 Antigens; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D007041:Hypoxanthine Phosphoribosyltransferase; D004318:Doxycycline