Adenine nucleotide - modulated CD8+ T cell differentiation and effector functions

Abstract

Stimulation of the T cell receptor with specific antigen leads to Ca2+ signaling in T cells which is essential for their function. Cyclic ADP ribose hydrolase (CD38), transient receptor potential cation channel subfamily M (TRPM) 2, purinergic ionotropic receptor (P2X) 4 and P2X7 are modulators of Ca2+ signaling which we hypothesized to be involved in activation and differentiation of T cells. We used CD38-deficient mice to investigate the role of CD38 in CD8+ T cells in vivo in Listeria monocytogenes infection models. In competitive T cell transfer experiments, Cd38-/- CD8+ T cells showed a disadvantage compared to wild type CD8+ T cells. The CD8+ T cell response to Listeria monocytogenes infection however, was not altered in Cd38-/- mice and we could not detect an altered phenotype of Cd38-/- CD8+ T cells. We could detect differentially expressed genes associated with an effector rather than memory state of Cd38-/- CD8+ T cells compared to wild type CD8+ T cells. In the publication "TRPM2 is not required for T cell function and differentiation" [Lory et al., 2022] we investigated the function of TRPM2 in T cells. We utilized in vitro T cell receptor stimulation, Listeria monocytogenes infection of TRPM2-deficient (Trpm2-/- ) mice and competitive T cell transfers which revealed TRPM2 does not affect CD8+ T cell function. We investigated the function of the purinergic ionotropic receptors P2X4 and P2X7 in CD4+ T cells in vitro. P2X4 deficient CD4+ T cells did not show an altered response to T cell receptor stimulation after 16 hours and in a proliferation assay. P2X7 deficient CD4+ T cells however showed reduced proliferation and reduced expression of the immediate early activation marker NUR77 after stimulation. The results are part of the publication "P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation" by Brock et al. [Brock et al., 2022] which focuses on the role of P2X4 and P2X7 in the formation of early localized Ca2+ microdomains. In conclusion, our results show that CD38 may be involved in the proliferation or survival of CD8+ T cells and development of memory T cells, P2X7 is important for activation and proliferation of CD4+ T cells and that TRPM2 is not required for CD8+ T cell function.