Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 431, Issue 24, Pages 4941-4958Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2019.10.019
Keywords
CD8; MHC; Structure; T-cell receptor; T cell
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Funding
- Swiss National Science Foundation [310030_12533/1]
- Czech Science Foundation [1506989S, RS 18-04871S]
- Ludwig Institute for Cancer Research
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The coreceptor CD8 alpha beta can greatly promote activation of T cells by strengthening T-cell receptor (TCR) binding to cognate peptide-MHC complexes (pMHC) on antigen presenting cells and by bringing p56(Lck) to TCR/CD3. Here, we demonstrate that CD8 can also bind to pMHC on the T cell (in cis) and that this inhibits their activation. Using molecular modeling, fluorescence resonance energy transfer experiments on living cells, biochemical and mutational analysis, we show that CD8 binding to pMHC in cis involves a different docking mode and is regulated by posttranslational modifications including a membrane-distal interchain disulfide bond and negatively charged O-linked glycans near positively charged sequences on the CD8 beta stalk. These modifications distort the stalk, thus favoring CD8 binding to pMHC in cis. Differential binding of CD8 to pMHC in cis or trans is a means to regulate CD8(+) T-cell responses and provides new translational opportunities. (C) 2019 The Author(s). Published by Elsevier Ltd.
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