Article: article from journal or magazin.
CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire.
Proceedings of the National Academy of Sciences of the United States of America
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.
Amino Acid Sequence, Animals, Antigenic Variation, CTLA-4 Antigen/deficiency, CTLA-4 Antigen/genetics, Cell Differentiation, Complementarity Determining Regions, Cytokines/biosynthesis, Dendritic Cells/cytology, Dendritic Cells/immunology, Encephalomyelitis, Autoimmune, Experimental/genetics, Encephalomyelitis, Autoimmune, Experimental/immunology, Female, Gene Rearrangement, T-Lymphocyte, Male, Mice, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Receptors, Antigen, T-Cell, alpha-beta/genetics, Self Tolerance, T-Lymphocytes/cytology, T-Lymphocytes/immunology, T-Lymphocytes, Regulatory/cytology, T-Lymphocytes, Regulatory/immunology, Thymus Gland/cytology, Thymus Gland/growth & development
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