Immunologic Research

, Volume 28, Issue 3, pp 241–253

CTLA-4 and tolerance

The biochemical point of view
  • Shunsuke Chikuma
  • Jeffrey A. Bluestone

DOI: 10.1385/IR:28:3:241

Cite this article as:
Chikuma, S. & Bluestone, J.A. Immunol Res (2003) 28: 241. doi:10.1385/IR:28:3:241


Potentially autoreactive T cells that escape negative selection in the thymus must be strictly controlled in the periphery to avoid autoimmune disease. The mostrobust 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 down regulate scytokine 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 aligand-independent manner. *** DIRECT SUPPORT *** A05Q2022 00011

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Shunsuke Chikuma
    • 1
  • Jeffrey A. Bluestone
    • 1
  1. 1.Diabetes CenterUniversity of California at San FranciscoSan Francisco

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