Trends in Immunology
Volume 36, Issue 2, February 2015, Pages 63-70
Journal home page for Trends in Immunology

Opinion
Confusing signals: Recent progress in CTLA-4 biology

https://doi.org/10.1016/j.it.2014.12.001Get rights and content
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Highlights

  • Cell extrinsic and cell intrinsic mechanisms of action of CTLA-4 are unclear.

  • Data suggest that the extracellular domain of CTLA4 elicits regulatory function.

  • The function of CTLA-4 tail may lie in regulating localization rather than signaling.

  • Membrane levels of CTLA-4 directly impact access of CD28 to shared ligands.

The mechanism of action of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remains surprisingly unclear. Regulatory T (Treg) cells can use CTLA-4 to elicit suppression; however, CTLA-4 also operates in conventional T cells, reputedly by triggering inhibitory signals. Recently, interactions mediated via the CTLA-4 cytoplasmic domain have been shown to preferentially affect Treg cells, yet other evidence suggests that the extracellular domain of CTLA-4 is sufficient to elicit suppression. Here, we discuss these paradoxical findings in the context of CTLA-4-mediated ligand regulation. We propose that the function of CTLA-4 cytoplasmic domain is not to transmit inhibitory signals but to precisely control the turnover, cellular location, and membrane delivery of CTLA-4 to facilitate its central function: regulating the access of CD28 to their shared ligands.

Keywords

CTLA-4
CD28
costimulation
T cell tolerance
T cell activation

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