Progressive change in expression of killer-like receptorsr and GPR56 expression defines the cytokine production potential of human CD4⁺ T memory cells

Abstract

Memory T cells mount an accelerated response upon re-challenge but are heterogeneous in phenotype and function. Traditionally memory T cells were classified into central memory, effector memory and terminally differentiated effector memory (T EMRA ) cells based on expression of CCR7 and CD45RA. Functional heterogeneity even within these subsets demonstrated the need for more suitable markers. We applied bulk and single gene expression profiling of human CD4 + memory T cells and identified surface markers, KLRB1, KLRG1, GPR56 and KLRF1, allowing classification into "low", "high" or "exhausted" cytokine producers. In contrast to common understanding KLRG1 expression was not associated with exhaustion and highest production of multiple cytokines was observed in KLRB1 + KLRG1 + GPR56 + T cells. Only additional KLRF1expression was associated with a decline in cytokine production. The superiority of KLRF1 to define exhausted cytokine producers compared to classical T EMRA identification was best exemplified for intrahepatic T cells in patients with inflammatory liver diseases.

The Novel Immune Checkpoint GPR56 Is Expressed on Tumor-Infiltrating Lymphocytes and Selectively Upregulated upon TCR Signaling

“…Interestingly, transcription factor Hobit was also found to be upregulated in GPR56-positive CD8 T cells isolated from tumor tissue vs. GPR56-positive CD8 T cells isolated from the blood or from normal adjacent tissue. The upregulated expression of transcriptional regulator Hobit was also previously observed in GPR56-positive CD4 TEMRA cells, with these cells also being more clonally expanded compared to the GPR56-negative fraction [33,[43][44][45]. In the current report, within PBL GPR56-positve fractions, a large portion of the cells featured a TEMRA phenotype, whereas in GPR56-positive TILs, a shift towards a TEM phenotype was observed.…”

Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance

“…Recent studies of CD4 + T EMRA cells have identified major subsets based on G protein-coupled receptor GPR56 expression, with virus-specific cells more frequently GPR56 + and more clonally expanded compared to GPR56 − cells (52). Increased expression of GPR56 and killer-like receptors (KLR) has been linked to higher cytokine expression by memory CD4 + T cells, including T cells obtained from liver tissue (53). CD4 + and CD8 + T EMRA cytotoxic T cells expressing GPR56 have also been associated with increased co-expression of CX 3 CR1 (52, 54, 55).…”