CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

被引:44
作者
Verhagen, Johan [1 ]
Genolet, Raphael [2 ]
Britton, Graham J. [1 ]
Stevenson, Brian J. [2 ,3 ]
Sabatos-Peyton, Catherine A. [1 ]
Dyson, Julian [4 ]
Luescher, Immanuel F. [2 ]
Wraith, David C. [1 ]
机构
[1] Univ Bristol, Sch Cellular & Mol Med, Bristol BS8 1TD, Avon, England
[2] Univ Lausanne, Ludwig Inst Canc Res, CH-1066 Epalinges, Switzerland
[3] Swiss Inst Bioinformat, Vital IT Grp, CH-1066 Lausanne, Switzerland
[4] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Immunol, London W12 0NN, England
基金
英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会;
关键词
costimulation; immune regulation; experimental autoimmune encephalomyelitis; MYELIN BASIC-PROTEIN; NEGATIVE SELECTION; CD28; COSTIMULATION; CD4(+)CD8(+) THYMOCYTES; PERIPHERAL HOMEOSTASIS; AUTOIMMUNE-DISEASE; SELF-TOLERANCE; CUTTING EDGE; ANTIGEN; IN-VITRO;
D O I
10.1073/pnas.1208573110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 V alpha and J alpha segment selection as well as CDR3 alpha 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.
引用
收藏
页码:E221 / E230
页数:10
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