Enhancing CD8 T-cell memory by modulating fatty acid metabolism.
CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T(E)) populations, followed by the persistence of long-lived memory (T(M)) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T(M) cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T(M)-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T(E)-cell responses, but have a profound defect in their ability to generate T(M) cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T(M)-cell generation in the absence of TRAF6. This treatment also increased CD8 T(M) cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.
Pearce
Erika L
EL
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Walsh
Matthew C
MC
Cejas
Pedro J
PJ
Harms
Gretchen M
GM
Shen
Hao
H
Wang
Li-San
LS
Jones
Russell G
RG
Choi
Yongwon
Y
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007156:Immunologic Memory / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D048029:TNF Receptor-Associated Factor 6; D008687:Metformin; D050721:Proto-Oncogene Proteins c-cbl