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

Immunity. 2012 Nov 16;37(5):854-66. doi: 10.1016/j.immuni.2012.07.012. Epub 2012 Oct 16.

Abstract

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.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / immunology
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Colitis / immunology
  • Colitis / metabolism
  • Endosomes / immunology
  • Endosomes / metabolism
  • Exocytosis / immunology
  • Golgi Apparatus / immunology
  • Golgi Apparatus / metabolism
  • Granzymes / immunology
  • Granzymes / metabolism*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Protein Transport
  • R-SNARE Proteins / immunology
  • R-SNARE Proteins / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Transport Vesicles / immunology
  • Transport Vesicles / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • CD4 Antigens
  • Interleukin-2 Receptor alpha Subunit
  • R-SNARE Proteins
  • Sybl1 protein, mouse
  • Interferon-gamma
  • Granzymes
  • sortilin