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.
Highlights
Despite the clinical success of blocking its interactions, how programmed cell death 1 (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)
CD8+ T cells from PDCD1−/− P14 T-cell receptor (TCR)-transgenic mice re-expressing PD-1 or vehicle spread on gp33:H2-Db surface (Fig. 1a–c), indicating that the antigen recognition machinery alone is able to support spreading without adhesion molecules used in most immunological synapse (IS) studies[32]
Together these data suggest that PD-1 suppresses the antigen recognition process that relies on binding of the TCR-CD8 axis to the cognate peptide-major histocompatibility complex (pMHC), an opposite effect to LFA-1 enhancement of IS formation
Summary
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). PD-1 signaling is initiated by the phosphorylation of its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) when PD-1 and the T-cell receptor (TCR) are co-engaged with their respective ligands This leads to the recruitment and activation of Src homology region 2 domain-containing phosphatases (SHPs), which attenuates the phosphorylation-dependent signaling cascades downstream of the TCR and the co-stimulatory receptor CD28, and thereby suppresses cellular functions such as activation, proliferation, metabolic regulation, cytotoxicity, and cytokine production[4,5,6,7,8]. These data reveal a mechanism in which PD-1 fine-tunes antigen recognition via “inside-out” negative feedback
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