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-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.
Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
Stefanie
S
Herda
Friederike
F
Raczkowski
Hans-Willi
HW
Mittrücker
Gerald
G
Willimsky
Kerstin
K
Gerlach
Anja A
AA
Kühl
Tilman
T
Breiderhoff
Thomas E
TE
Willnow
Bernd
B
Dörken
Uta E
UE
Höpken
Armin
A
Rehm
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005089:Exocytosis / Q000276:immunology; D006056:Golgi Apparatus / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D050683:R-SNARE Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D022161:Transport Vesicles / Q000276:immunology / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D015704:CD4 Antigens; D053804:Granzymes; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D050683:R-SNARE Proteins; D000099183:Sortilin; C496927:Sybl1 protein, mouse