Dysregulation of T cell intrinsic C5aR2 activation causes uncontrolled inflammatory Th responses and autoinflammatory syndrome

Liver-derived systemic complement guards the vascular space, while cell intrinsic and/or intracellularly derived complement components play pivotal roles in tissue immunity through the regulation of normal cell physiology, metabolism, survival and effector functions in T cells. In human Th cells, intracellular C3 and C5 and their respective receptors C3aR1 and C5aR1 drive T cell homeostatic survival and normal Th1 IFN-γ production, respectively.  Here we define a role for the alternative C5a receptor, C5aR2, 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 C5aR2 ligand (C5adesArg) 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. Further, Cpm or C5ar2-deficient CD4 T cells displayed largely overlapping gene signature perturbations. In line with these observations, Cpm^KO 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 critical and complex autoregulatory functions of the cell-autonomous complement C5 system in T cell responses.