CTLA-4 and Tolerance: The Biochemical Point of View

Shunsuke Chikuma, Jeffrey A. Bluestone

Research output: Contribution to journalReview articlepeer-review

71 Citations (Scopus)


Potentially autoreactive T cells that escape negative selection in the thymus must be strictly controlled in the periphery to avoid autoimmune disease. The most robust regulatory process controlling autoreactivity is mediated by the CTLA-4-B7 pathway. The critical homeostasis mediated by CTLA-4 was proven using monoclonal antibodies and genetically disrupted CTLA-4 knockout mice that develop polyclonal lymphocyte activation and proliferation leading to massively enlarged lymph nodes and spleen and fatal multiorgan lymphocytic infiltrates. CTLA-4 ligation following T-cell activation downregulates cytokine production and cell-cycle progression, however, the proximal biochemical basis for robust T-cell regulation remains unclear. In this review, we summarize studies supporting a dynamic role for CTLA-4 at the immunological synapse leading to direct attenuation of early cell signals. A model is proposed based on these observations, which proposes that CTLA-4 may, in fact, function under some circumstances in a ligand-independent manner.

Original languageEnglish
Pages (from-to)241-253
Number of pages13
JournalImmunologic Research
Issue number3
Publication statusPublished - 2003
Externally publishedYes


  • CTLA-4
  • Costimulation
  • Lipid rafts
  • Tolerance

ASJC Scopus subject areas

  • Immunology


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