The Inhibitory Receptor GPR56 (Adgrg1) Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo

Abstract

Tissue-resident memory T (TRM) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of TRM cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions. Here, we explored the expression pattern, expression regulation, and function of GPR56 on pathogen-specific CD8+ T cells using two infection models. We observed that GPR56 is expressed on TRM cells during acute infection and is upregulated by the TRM cell-inducing cytokine TGF-β and the TRM cell-associated transcription factor Hobit. However, GPR56 appeared dispensable for CD8+ T-cell differentiation and function upon acute infection with LCMV as well as Listeria monocytogenes. Thus, TRM cells specifically acquire the inhibitory receptor GPR56, but the impact of this receptor on TRM cells after acute infection does not appear essential to regulate effector functions of TRM cells.

The adhesion G protein‐coupled receptor GPR56/ADGRG1 in cytotoxic lymphocytes

“…TGF-β strongly upregulates expression of Adgrg1, and reciprocally, expression of Adgrg1 is reduced in skin T RM cells of mice lacking a functional TGF-β receptor II. 40 Thus, the transcription factors HOBIT and the T RM cell-inducing cytokine TGF-β contribute to the expression of Adgrg1 in cytotoxic lymphocytes.…”

“…In particular, GPR56 is upregulated in herpes simplex virus (HSV)‐specific T RM cells of the skin and in lymphocytic choriomeningitis virus (LCMV)‐specific T RM cells across several organs (Figure 2A). 40,44,45 …”

“…We have recently addressed the contribution of GPR56 in the regulation of mouse pathogen‐specific T RM cells 40 . Analysis of pathogen‐specific CD8 + T‐cell responses in Adgrg1 knockout animals after acute infection with LCMV and Listeria monocytogenes did not reveal an essential inhibitory role of GPR56 in the regulation of proliferative, cytokine, or cytotoxic responses of CD8 + T RM cells.…”

A guide to adhesion GPCR research

“…Moreover, GPR56/ADGRG1 is a surrogate marker and regulator of the cytotoxic capacity of human lymphocytes [144], and negatively regulates natural killer (NK)‐cell effector functions [145]. Tissue‐resident memory T cells, which are controlled by a multitude of inhibitory receptors, express GPR56/ADGRG1 [146,147]. In the brain, GPR56/ADGRG1 is also expressed by healthy, but downregulated by disease‐associated microglia [148], and a splice variant of it has been demonstrated to mediate microglia‐mediated synaptic pruning [72].…”

“…ADGRG1 [146,147]. In the brain, GPR56/ADGRG1 is also expressed by healthy, but downregulated by disease-associated microglia [148], and a splice variant of it has been demonstrated to mediate microgliamediated synaptic pruning [72].…”