Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation.
Autophagy regulates cell differentiation, proliferation, and survival in multiple cell types, including cells of the immune system. In this study, we examined the effects of a disruption of autophagy on the differentiation of invariant NKT (iNKT) cells. Using mice with a T lymphocyte-specific deletion of Atg5 or Atg7, two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell-derived IFN-γ. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells.
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
Bo
B
Pei
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
Meng
M
Zhao
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Brian C
BC
Miller
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
Jose Luis
JL
Véla
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Monique W
MW
Bruinsma
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Herbert W
HW
Virgin
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and mitch@liai.org.
Mitchell
M
Kronenberg
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D013481:Superoxides; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7