Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.
Appropriate development of regulatory T (Treg) cells is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg cell development. It is unclear what these missing factors are. However, signals emanating from the T cell receptor (TCR), the costimulatory receptor CD28, and the family of gammac-dependent cytokine receptors are required for Treg cell development. Herein we demonstrate that expression of a constitutively active Stat5b transgene (Stat5b-CA) allowed for Treg cell development in neonatal mice and restored Treg cell numbers in Cd28(-/-) mice. Sequence analysis of TCR genes in Stat5b-CA Treg cells indicated that ectopic STAT5 activation resulted in a TCR repertoire that more closely resembled that of naive T cells. Using MHCII tetramers to identify antigen-specific T cells, we showed that STAT5 signals diverted thymocytes normally destined to become naive T cells into the Treg cell lineage. Our data support a two-step model of Treg cell differentiation in which TCR and CD28 signals induce cytokine responsiveness and STAT5-inducing cytokines then complete the program of Treg cell differentiation.
Burchill
Matthew A
MA
Department of Laboratory Medicine and Pathology, Center for Immunology, The Cancer Center, University of Minnesota, 312 Church Street SE, 6-116 Nils Hasselmo Hall, Minneapolis, MN 55455 USA.
Yang
Jianying
J
Vang
Kieng B
KB
Moon
James J
JJ
Chu
H Hamlet
HH
Lio
Chan-Wang J
CW
Vegoe
Amanda L
AL
Hsieh
Chyi-Song
CS
Jenkins
Marc K
MK
Farrar
Michael A
MA
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D017421:Sequence Analysis; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
D018106:CD28 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse