title: Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.
abstract: 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.
authors.affiliation: 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.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Burchill
authors.forename: Jianying
authors.initials: J
authors.lastname: Yang
authors.forename: Kieng B
authors.initials: KB
authors.lastname: Vang
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: H Hamlet
authors.initials: HH
authors.lastname: Chu
authors.forename: Chan-Wang J
authors.initials: CW
authors.lastname: Lio
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Vegoe
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
mesh_terms: 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*
chemical_list: 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