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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 V? and J? segment selection as well as CDR3? 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.

SUBMITTER: Verhagen J 

PROVIDER: S-EPMC3549118 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Verhagen Johan J   Genolet Raphaël R   Britton Graham J GJ   Stevenson Brian J BJ   Sabatos-Peyton Catherine A CA   Dyson Julian J   Luescher Immanuel F IF   Wraith David C DC  

Proceedings of the National Academy of Sciences of the United States of America 20121224 3


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  ...[more]

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