Control of IFN-γ response via autocrine activation of the C5a complement receptors and the NLRP3 inflammasome within human T lymphocytes

IL-1β is a pro-inflammatory cytokine critical for the protection against pathogens. The NLRP3 inflammasome mediates the maturation of IL-1β, however uncontrolled inflammasome activity contributes to the development of several diseases with strong impact on public health. The complement system is involved in the direct elimination of pathogens and in shaping adaptive immune responses. Particularly, paracrine and/or autocrine signals mediated by the complement fragments C3a and C3b regulate the induction and contraction of human Th1 responses. The function of C5a in T cells was still unexplored. Preliminary evidences supported a role for C5a in modulating the NLRP3 inflammasome. This thesis investigates the potential function of autocrine complement C5amediated signals and the NLRP3 inflammasome within human CD4+ T cells during Th1 effector responses. This work demonstrates that intracellular C5 activation (driven by T cell receptor and CD46 signaling) and C5aR1 engagement induce ROS production. These events lead to T cell intrinsic NLRP3 inflammasome activation and IL-1β secretion, which support IFN-γ production and Th1 induction in an autocrine fashion. Surfaceexpressed C5aR2 negatively regulates this process. CD4+ T cells from patients with cryopyrin associated periodic syndrome (CAPS), which have mutated, constitutively-active, NLRP3 inflammasome, had overactive in vitro Th1 responses, normalised by NLRP3 inhibition. In collaboration with Dr. Erin West (NIH, MD, USA), in vivo significance of NLRP3 inflammasome activity within T cells was shown using models of viral infection, colitis and graft versus host disease (GvHD). Together, these data indicate the requirement for intrinsic NLRP3 activation for normal Th1 induction in mouse and human CD4+ T cells. This work resulted in the publication of a peer-reviewed original research article entitled “T helper 1 immunity requires complement-driven, NLRP3 inflammasome activity in CD4+ T cells” in Science (Arbore et al., 2016), which is incorporated in this thesis. Finally, in the last thesis chapter, it has been investigated whether optimal production of IFN-γ by CD8+ T cells also relies on autocrine complement and NLRP3 inflammasome activities