title: Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease.
abstract: It is generally acknowledged that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4/CD152) plays a pivotal role in the regulation of T-cell activation and the establishment of self-tolerance in the periphery. CTLA-4-deficient (CTLA-4KO) mice develop a lymphoproliferative disorder and die within 4 weeks of birth, suggesting a role for CTLA-4 in T-cell homeostasis or the development and activity of T-regulatory (Treg) cells. To study the role of CTLA-4 in the control of experimental autoimmune encephalomyelitis (EAE), we have generated a CTLA-4KO mouse in which >90% of all CD4(+) T cells bear a Vbeta8.2 transgenic T-cell receptor that is specific for myelin basic protein peptide Ac1-9 (ASQKRPSQR). These mice do not develop spontaneous lymphoproliferative disease or EAE and are resistant to disease induction. This correlates with a higher frequency of functional FoxP3(+) Treg cells in the spleen and thymus of CTLA-4KO mice. The absence of CTLA-4-mediated suppression of CD28 signaling resulted in the early expression of FoxP3 on double-positive cells in the thymic cortex. We conclude that CTLA-4 is not essential for the peripheral function of FoxP3(+) Treg cells but plays a pivotal role in their thymic selection.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol School of Medical Sciences, Bristol BS8 1TD, United Kingdom. johan.verhagen@bristol.ac.uk
authors.forename: Johan
authors.initials: J
authors.lastname: Verhagen
authors.forename: Leona
authors.initials: L
authors.lastname: Gabrysová
authors.forename: Sophie
authors.initials: S
authors.lastname: Minaee
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sabatos
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism*; D017353:Gene Deletion; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit