title: CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance.
abstract: Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.forename: David S
authors.initials: DS
authors.lastname: Brown
authors.forename: Hai
authors.initials: H
authors.lastname: Nguyen
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
authors.forename: Jinhee
authors.initials: J
authors.lastname: Lee
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Appleby
authors.forename: Sandy D
authors.initials: SD
authors.lastname: Der
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Chambers
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001973:Bromodeoxyuridine; D060908:CTLA-4 Antigen; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D001973:Bromodeoxyuridine