Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells

Abstract

All memory T cells mount an accelerated response on antigen reencounter, but significant functional heterogeneity is present within the respective memory T-cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, including KLRB1, KLRG1, GPR56, and KLRF1, help define low, high, or exhausted cytokine producers within human peripheral and intrahepatic CD4+ memory T-cell populations. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with T-cell exhaustion and reduced TNF/IFN-γ production. Lastly, TCRβ repertoire analysis and in vitro differentiation support a regulated, progressive expression for these markers during CD4+ memory T-cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development.Despite the current human CD4 memory T cell stratification by CD45RA/CCR7, functional heterogeneities still exist within the respective subsets. Here the authors show that several surface markers, including KLRB1, KLRG1, GPR56 and KLRF1, help to further refine the subsetting of human CD4 memory T cells and provide insights for their differentiation.