Perturbations in the T cell-intrinsic complement C5 program cause uncontrolled inflammatory Th responses and autoinflammatory syndrome 2735

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Abstract Description Systemic complement guards the vascular space, while cell intrinsic and/or intracellularly derived complement components C3 and C5 play pivotal roles in tissue immunity through the regulation of normal cell physiology and metabolism. In human Th cells, cell-autonomous C5a generation engages the intracellular C5aR1, which triggers Th1 program-supporting intrinsic NLRP3 activation. Here, we define a role for the alternative C5a receptor, C5aR2 (which is activated by C5a-desArg), in restraining T helper cell effector responses by assessing T cells from the first described patient with C5aR2 deficiency. This patient suffers from an autoinflammatory syndrome, with enhanced inflammatory Th responses, a profound loss of naïve CD4 T cells, and a preponderance of memory T cells. Furthermore, we identified T cell-intrinsic carboxypeptidase M (CPM) as the C5a-desArg/C5aR2 ligand generating enzyme. In consequence, CPM inhibition, or genetic deletion of CPM, resulted in enhanced inflammatory human T cell responses that were rescued by a C5aR2 agonist in vitro. Further, Cpm or C5ar2-deficient mouse CD4 T cells displayed largely overlapping gene signature perturbations. In line with these observations, Cpm–/– CD4 T cells transferred into mice caused increased pathology vs. WT CD4 T cells in a T cell transfer model of colitis. Overall, these findings highlight the importance of an unexpected, CPM-controlled, autoregulatory C5aR1 and C5aR2 signaling balance to limit pathological Th1 immunity. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

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