PVRIG

PVRIG (CD112R) is a coinhibitory immune checkpoint receptor expressed on T cells and NK cells that restrains antitumor immunity by engaging the nectin ligand PVRL2 (CD112/Nectin-2) (PMID:26755705, PMID:30659055). On T cells, PVRIG binds PVRL2 and competes with the costimulatory receptor CD226 for ligand, and its engagement dampens TCR-mediated signaling; disrupting the PVRIG-PVRL2 interaction enhances CD8+ T cell cytokine production and cytotoxicity (PMID:26755705, PMID:30659054). The PVRIG-PVRL2 axis is nonredundant with the TIGIT-PVR axis, with PVRL2-mediated T cell inhibition transmitted specifically through PVRIG rather than TIGIT, such that combined PVRIG, TIGIT, or PD-1 blockade gives additive activation (PMID:30659054). Structurally, PVRIG achieves high-affinity, selective recognition of Nectin-2 through a unique CC' loop that supports a double-lock-and-key binding mode and charged F-strand residues that discriminate Nectin-2 from CD155/PVR (PMID:38626767). On NK cells, PVRIG blockade enhances ADCC and cytotoxicity and reverses NK cell exhaustion, and genetic and depletion studies establish an NK-cell-intrinsic, T cell-independent antitumor mechanism (PMID:28623459, PMID:34174928). Surface PVRIG is downregulated upon NK cell activation while the protein is continuously trafficked from the ER and Golgi to the cell surface, with a larger cytoplasmic than surface pool (PMID:33147937). Epistasis analysis places PVRIG within the broader immunosuppressive activity of PVRL2, as PVRL2 deletion suppresses tumor growth even without PVRIG and PVRIG loss confers no further benefit in the absence of PVRL2 (PMID:38588410).

1. 2016 High

   Established PVRIG as a coinhibitory receptor on T cells, identifying its ligand and its competition with the activating receptor CD226 — defining the molecular basis of a new inhibitory axis.

   Evidence Receptor-ligand and competition binding assays with CD226, plus TCR-signaling functional readouts in human T cells

   PMID:26755705

   Open questions at the time

   • Downstream signaling motifs transmitting the inhibitory signal not defined
   • Did not resolve relative contributions of PVRIG vs. CD226 in physiological settings
2. 2017 Medium

   Extended PVRIG function to NK cells, showing blockade augments antibody-dependent cytotoxicity and distinguishing its expression pattern from TIGIT.

   Evidence Flow cytometry and NK cell ADCC/cytotoxicity assays with PVRIG and TIGIT antibody blockade

   PMID:28623459

   Open questions at the time

   • Single-lab functional data
   • Mechanism of NK inhibition not dissected at signaling level
3. 2019 High

   Demonstrated that PVRL2-mediated inhibition of CD8+ T cells runs specifically through PVRIG and not TIGIT, establishing PVRIG-PVRL2 as a nonredundant node combinable with TIGIT and PD-1 blockade.

   Evidence Selective antibody blockade of PVRIG/TIGIT/PD-1 with CD8+ T cell cytokine, cytotoxicity, and TIL functional assays

   PMID:30659054

   Open questions at the time

   • Did not establish ligand selectivity at structural level
   • Combination synergy mechanism not mapped
4. 2019 High

   Genetic knockout confirmed PVRIG as a bona fide inhibitory receptor in vivo, with PVRL2 as principal ligand and weak PVR binding, and defined the receptor/ligand cellular compartments in the tumor microenvironment.

   Evidence PVRIG knockout mice, Listeria infection and tumor models, binding assays, flow cytometry for receptor/ligand expression

   PMID:30659055

   Open questions at the time

   • Functional consequence of weak PVR interaction unresolved
   • Cell-intrinsic signaling output not characterized
5. 2021 High

   Resolved whether PVRIG blockade efficacy depends on adaptive immunity by showing an NK-cell-intrinsic, T-cell-independent antitumor mechanism that reverses NK and CD8+ T cell exhaustion.

   Evidence PVRIG-deficient and Rag1-/- mice with NK/CD8 depletion across syngeneic and xenograft tumor models

   PMID:34174928

   Open questions at the time

   • Molecular basis of exhaustion reversal not defined
   • Relative NK vs. T contribution context-dependent
6. 2021 Medium

   Defined PVRIG subcellular dynamics, showing a predominantly cytoplasmic pool, continuous ER/Golgi-to-surface trafficking, and surface downregulation upon NK activation.

   Evidence Surface vs. cytoplasmic flow cytometry, trafficking inhibitors, immunofluorescence, multiple NK activation stimuli

   PMID:33147937

   Open questions at the time

   • Trafficking regulatory machinery unidentified
   • Functional consequence of activation-induced downregulation unclear
   • Single lab
7. 2024 High

   Crystal structure of the PVRIG-Nectin-2 complex defined the structural determinants of high-affinity binding and ligand selectivity.

   Evidence X-ray crystallography of PVRIG-Nectin-2 complex with binding affinity comparisons across co-receptors and ligands

   PMID:38626767

   Open questions at the time

   • Structure does not address intracellular signaling
   • Apo PVRIG conformation and competitive interface with CD226 not co-resolved
8. 2024 Medium

   Tested a therapeutic Fc-competent anti-PVRIG antibody, showing blockade preferentially drives NK cell activation and that Fc effector function is critical for efficacy.

   Evidence SPR/ELISA binding (Kd 0.53 nM), in vitro NK and T cell assays, in vivo tumor models with depletion and Fc-effector analysis

   PMID:38554184

   Open questions at the time

   • Single-lab antibody-specific findings
   • Mechanistic basis for NK-over-T selectivity not resolved
9. 2024 High

   Genetic epistasis placed PVRIG within the broader immunosuppressive activity of PVRL2, showing PVRL2 acts through PVRIG-independent routes and PVRIG loss adds nothing without PVRL2.

   Evidence PVRL2 and PVRIG single and double knockout syngeneic tumor models with immune cell depletion

   PMID:38588410

   Open questions at the time

   • Identity of additional PVRL2 receptors mediating PVRIG-independent suppression not defined
   • Pathway hierarchy in human disease not validated

• The intracellular signaling cascade by which PVRIG transmits its inhibitory signal upon PVRL2 engagement remains uncharacterized in the available corpus.
• No cytoplasmic-domain signaling motifs or downstream effectors identified
• Mechanism of CD226 antagonism at the signaling level unresolved