Björn-Philipp Diercks

During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca 2+ microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca 2+ microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP 3 R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca 2+ microdomains required the concerted activity of two to six IP 3 Rs and ORAI1 channels to achieve the increase in the Ca 2+ concentration in the ER–plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca 2+ microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca 2+ response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca 2+ microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.

Extracellular ATP activates the P2X7 receptor, leading to inflammasome activation and release of pro‐inflammatory cytokines in monocytes. However, a detailed analysis of P2X7 receptor expression and function in the human T cell compartment has not been reported. Here, we used a P2X7‐specific nanobody to assess cell membrane expression and function of P2X7 on peripheral T lymphocyte subsets. The results show that innate‐like T cells, which effectively react to innate stimuli by secreting high amounts of pro‐inflammatory cytokines, have the highest expression of P2X7 in the human T cell compartment. Using Tγδ cells as example for an innate‐like lymphocyte population, we demonstrate that these cells are more sensitive to P2X7 receptor activation than conventional T cells, affecting fundamental cellular mechanisms like calcium signaling and ATP‐induced cell death. The increased susceptibility of innate‐like T cells to P2X7‐mediated cell death provides a mechanism to control their homeostasis under inflammatory conditions. Understanding the expression and function of P2X7 on human immune cells is essential to assume the benefits and consequences of newly developed P2X7‐based therapeutic approaches.