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

Yang Liu; Michel A Cuendet; Laurence Goffin; Radek Šachl; Marek Cebecauer; Luca Cariolato; Philippe Guillaume; Patrick Reichenbach; Melita Irving; George Coukos; Immanuel F Luescher

doi:10.1016/j.jmb.2019.10.019

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

J Mol Biol. 2019 Dec 6;431(24):4941-4958. doi: 10.1016/j.jmb.2019.10.019. Epub 2019 Nov 5.

Affiliations

¹ Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University Hospital of Lausanne, 1009, Lausanne, Switzerland.
² Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University Hospital of Lausanne, 1009, Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, USA.
³ Department of Biophysical Chemistry, J. Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences, 18223 Prague, Czech Republic.
⁴ Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University Hospital of Lausanne, 1009, Lausanne, Switzerland. Electronic address: [email protected].

PMID: 31704286
DOI: 10.1016/j.jmb.2019.10.019

Abstract

The coreceptor CD8αβ 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 CD8β 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.

Keywords: CD8; MHC; Structure; T cell; T-cell receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
CD8 Antigens / chemistry
CD8 Antigens / genetics
CD8 Antigens / metabolism*
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism*
Histocompatibility Antigens / chemistry*
Histocompatibility Antigens / genetics
Histocompatibility Antigens / immunology*
Lymphocyte Activation / immunology
Mice
Mice, Knockout
Models, Biological
Models, Molecular
Multiprotein Complexes / chemistry
Multiprotein Complexes / immunology
Multiprotein Complexes / metabolism*
Mutation
Peptides / chemistry
Peptides / immunology
Peptides / metabolism*
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
Structure-Activity Relationship

Substances

CD8 Antigens
Histocompatibility Antigens
Multiprotein Complexes
Peptides