T cell-intrinsic C5L2 activation protects against uncontrolled inflammatory Th responses and autoimmunity

Abstract Intracellular/autocrine complement proteins have emerged as critical regulators of human Th1 induction and contraction. T cells contain both intracellular C3 C5 activation systems, with C3aR1 C5aR1 stimulation driving cell homeostatic survival normal IFNg production, respectively. Here we demonstrate how the intracellular/autocrine system is regulated by using from first described patient C5aR2 deficiency. This suffers an autoinflammatory syndrome, enhanced inflammatory Th responses a profound loss naïve CD4 in blood (95% memory phenotype). Thus, contrast to stimulation, surface expressed important negative regulator induction. While can bind C5a, found that carboxypeptidase-processed form C5a-desArg, was twice potent C5a reducing In addition, carboxypeptidase M (CPM) expression highly induced upon indicating CPM may be mediating cell-derived C5a-desArg generation stimulation. this vein, CRISPR/Cas9 generated CPMKO cells, or presence inhibitor, hyper-induction, which rescued addition agonist reduced adding but not C5a. The vivo importance cell-expressed autocrine demonstrated Cpm −/−mice increased pathology caused −/−T transfer colitis model. These data highlight regulation through signaling responses.