PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition

Kaitao Li, Zhou Yuan, Jintian Lyu, Eunseon Ahn, Simon J. Davis, Rafi Ahmed and Cheng Zhu ()
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Kaitao Li: Georgia Institute of Technology
Zhou Yuan: Georgia Institute of Technology
Jintian Lyu: Georgia Institute of Technology
Eunseon Ahn: Emory University School of Medicine
Simon J. Davis: University of Oxford, John Radcliffe Hospital, Headington
Rafi Ahmed: Emory University School of Medicine
Cheng Zhu: Georgia Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Despite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1’s targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR–pMHC–CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1’s potent inhibitory function and its value as a target for clinical intervention.

Date: 2021
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DOI: 10.1038/s41467-021-22965-9

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