The Sorting Receptor Sortilin Exhibits a Dual Function in Exocytic Trafficking of Interferon-γ and Granzyme A in T Cells

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

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (151 K)Download as PowerPoint slideHighlights► Sortilin controls distinct exocytic routes in CD4+CD8+ T and NK lymphocytes ► Loss of Sortilin reveals differential transport mechanisms for granzyme A and B ► IFN-γ transit from the Golgi complex to early endosomes is Sortilin dependent ► Sortilin deletion enhances susceptibility for infection but limits autoimmune colitis