The adhesion G protein-coupled receptor GPR56/ADGRG1 is an inhibitory receptor on human NK cells

Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. We here explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit, a homolog of Blimp-1, and declined upon cell activation. Through studying NK cells from polymicrogyria patients with disease-causing mutations in the ADGRG1 gene, encoding GPR56, and NK-92 cells ectopically expressing the receptor, we found that GPR56 negatively regulates immediate effector functions, including production of inflammatory cytokines and cytolytic proteins, degranulation, and target cell killing. GPR56 pursues this activity by associating with the tetraspanin CD81. We conclude that GPR56 inhibits natural cytotoxicity of human NK cells

The Costimulatory Molecule CD27 Maintains Clonally Diverse CD8+ T Cell Responses of Low Antigen Affinity to Protect against Viral Variants

SummaryCD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8+ T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8+ T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8+ T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8+ T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8+ T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens