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doi: 10.1016/j.immuni.2014.11.005. Epub 2014 Nov 20.Balance and imbalance in the immune system: life on the edge
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- PMID:25517610
- PMCID: PMC4710093
- DOI: 10.1016/j.immuni.2014.11.005
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Comment
Balance and imbalance in the immune system: life on the edge
Suzanne L Topalian et al. Immunity..
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Abstract
CTLA-4 is a key immune checkpoint in maintaining self-tolerance, which can be co-opted by cancer to evade immune attack. In Science, Kuehn et al. (2014) describe clinical manifestations from inherited heterozygous CTLA4 mutations, and some are reminiscent of immune-related consequences from anti-CTLA-4 cancer therapy.
Copyright © 2014 Elsevier Inc. All rights reserved.
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In naive T lymphocytes from healthyCTLA4+/+ individuals, TCR signaling in response to cognate antigen is accompanied by CD28 costimulation, resulting in the rapid induction of inhibitory CTLA-4 coreceptors on the cell surface. CTLA-4 has a higher affinity for the ligands CD80 and CD86 than for CD28. Therefore, a switch to negative signaling occurs to inhibit T cell activation and appropriately conclude the immune response. In contrast, CTLA-4-haploinsufficient patients express reduced levels of CTLA-4 on activated T effector cells. This alters the balance between stimulatory CD28 and inhibitory CTLA-4 signals, sustaining the activation and proliferation of antigen-specific T cells and leading to autoimmunity. pMHC, peptide major histocompatibility complex.
Comment on
- Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G.Kuehn HS, et al.Science. 2014 Sep 26;345(6204):1623-1627. doi: 10.1126/science.1255904. Epub 2014 Sep 11.Science. 2014.PMID:25213377Free PMC article.
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