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

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 KLRF1 expression 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.