CD8 Binding of MHC-Peptide Complexes in cis or trans Regulates CD8+ T-cell Responses

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Liu, Yang^1,2  Cuendet, Michel A.^1,2,3,4  Goffin, Laurence^1,2  Sachl, Radek⁵  Cebecauer, Marek⁵  Cariolato, Luca^1,2  Guillaume, Philippe^1,2  Reichenbach, Patrick^1,2  Irving, Melita^1,2  Coukos, George^1,2  Luescher, Immanuel F.^1,2 

[1] Univ Lausanne, Ludwig Inst Canc Res, CH-1009 Lausanne, Switzerland

[2] Univ Hosp Lausanne, Dept Oncol, CH-1009 Lausanne, Switzerland

[3] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[4] Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA

[5] Czech Acad Sci, J Heyrovsky Inst Phys Chem, Dept Biophys Chem, Prague 18223, Czech Republic

关键词: CD8;    MHC;    Structure;    T-cell receptor;    T cell;   

DOI  :  10.1016/j.jmb.2019.10.019

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free