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

Johan Verhagen*, Raphaël Genolet, Graham J Britton, Brian J Stevenson, Catherine A Sabatos-Peyton, Julian Dyson, Immanuel F Luescher, David C Wraith

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

34 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)E221-E230
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number3
Early online date24 Dec 2012
DOIs
Publication statusPublished - 15 Jan 2013

Keywords

  • 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 4
  • IN-VITRO

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