The effect of interleukin 7 on CD8+T cell accumulation and differentiation in the presence of adenosine signaling

Abstract

Cytotoxic T cells are important cytotoxic adaptive immune cells. Their role is to check every single cell for protecting the body against microbial infections. They are also the main players for antigen-specific recognition and elimination of cancer cells. The ability of the cancer cells to inhibit those cells, is very important to diagnose the severity of the tumors. Therefore, tumor microenvironment analysis is the key factor that need to be taken account before intervention to the tumor. Stress, cell damage, and ischemia, often seen in the tumor microenvironment, cause the release and accumulation of adenosine in the extracellular space. Therefore, extracellular adenosine levels are higher in the tumor microenvironments than adjacent normal tissues. Adenosine can target four subtypes of G protein-coupled receptors; A1, A2A, A2B and A3 adenosine receptors. Adenosine signaling causes inhibition of immune cells from both innate and adaptive compartments through adenosine A2A and A2B receptors (A2AR and A2BR, respectively). A2AR is the main receptor subtype expressed by cytotoxic T cells. Interleukin 7 (IL-7) is a cytokine expressed by immune cells and stromal cells. IL-7 is important for the regulation of T cell maintenance and memory differentiation. Previous studies have shown that global or T cell-specific deletion of Adora2a (A2AR gene) may unexpectedly promote growth of syngeneic B16 melanoma, which is associated with reduced T cell accumulation and IL7 receptor alpha (CD127) expression in tumor associated T cells. In this study we tested the effect of adenosine signaling in the presence or absence of IL-7 or in some cases IL-2 on CD8+ T cell accumulation and differentiation in vitro. Adenosine signaling inhibited accumulation and IL-2 receptor expression of CD8+T cells while partially sustaining the IL-7 receptor expression. Addition of IL-7 but not IL-2 to the cell culture completely reversed the adenosine-mediated reduction in T cell accumulation. In addition, adenosine signaling reduced the expression of T cell exhaustion marker PD-1 in the presence of IL7 but not IL-2. Finally, adenosine signaling differentiated CD8+T cells towards central memory phenotype rather than effector/effector memory phenotype. Addition of IL-7 or IL-2 did not change this effect. In summary, adenosine cross-talk with IL-7 is important for CD8 T cell phenotypic differentiation and accumulation, which may have important implications in in vivo conditions.