title: CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire.
abstract: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3(+) regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3(+) Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4(+)CD8(-) thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.
authors.affiliation: School of Cellular and Molecular Medicine,  University of Bristol, Bristol BS8 1TD,  United Kingdom.
authors.forename: Johan
authors.initials: J
authors.lastname: Verhagen
authors.forename: Raphaël
authors.initials: R
authors.lastname: Genolet
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Britton
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sabatos-Peyton
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation; D060908:CTLA-4 Antigen / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D022801:Complementarity Determining Regions; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D022801:Complementarity Determining Regions; C556707:Ctla4 protein, mouse; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta