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-? upon infections and in autoimmune colitis. Exit of interferon-? from the Golgi apparatus required the presence of Sortilin. Furthermore, we tracked the transport route of interferon-? beyond this Sortilin-dependent Golgi to early endosome step. In wild-type T cells, trafficking of interferon-? from the endosomal sorting platform to the plasma membrane proceeded independently of recycling endosomes, and interferon-? remained excluded from late endosomes. Our results suggest that Sortilin modulates systemic immune responses through exocytic sorting of immunological effector molecules.
