The sorting receptor sortilin exhibits a dual function in exocytic trafficking of interferon-γ and granzyme A in T cells

Immunological control of infections or tumors depends on the release of effector cytokines and polarized secretion of cytotoxic granules from T cells and natural killer cells. Here we show that the sorting receptor Sortilin controlled both processes. In murine Sortilin-deficient cytotoxic T lymphocytes, regulated secretion of granzyme A and cytotoxic killing was enhanced and correlated with increased vesicle-associated membrane protein 7 availability. In contrast, loss of Sortilin reduced the release of interferon-{gamma} upon infections and in autoimmune colitis. Exit of interferon-{gamma} from the Golgi apparatus required the presence of Sortilin. Furthermore, we tracked the transport route of interferon-{gamma} beyond this Sortilin-dependent Golgi to early endosome step. In wild-type T cells, trafficking of interferon-{gamma} from the endosomal sorting platform to the plasma membrane proceeded independently of recycling endosomes, and interferon-{gamma} remained excluded from late endosomes. Our results suggest that Sortilin modulates systemic immune responses through exocytic sorting of immunological effector molecules.