Publication Date:
2009-06-06
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803086/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803086/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearce, Erika L -- Walsh, Matthew C -- Cejas, Pedro J -- Harms, Gretchen M -- Shen, Hao -- Wang, Li-San -- Jones, Russell G -- Choi, Yongwon -- R01 AI064909/AI/NIAID NIH HHS/ -- R01 AI064909-04/AI/NIAID NIH HHS/ -- T32 CA009140/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jul 2;460(7251):103-7. doi: 10.1038/nature08097. Epub 2009 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494812" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing/deficiency/genetics
;
Animals
;
CD8-Positive T-Lymphocytes/cytology/drug effects/*immunology/*metabolism
;
Fatty Acids/*metabolism
;
Hypoglycemic Agents/pharmacology
;
Immunologic Memory/*immunology
;
Listeria monocytogenes/immunology
;
Listeriosis/immunology/metabolism/microbiology
;
Metformin/pharmacology
;
Mice
;
Mice, Inbred C57BL
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Proto-Oncogene Proteins c-cbl/deficiency/genetics
;
TNF Receptor-Associated Factor 6/*deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
