Enhancing CD8 T Cell Memory by Modulating Fatty Acid Metabolism

By Erika L. Pearce, M. Walsh, P. Cejas, G. Harms, Hao Shen, Li-San Wang, Russell G. Jones, Yongwon Choi. Nature, 2009

1,547 citations recorded by the source corpus.

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 (TE) populations, followed by the persistence of long-lived memory (TM) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to TM 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 TM-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 TE-cell responses, but have a profound defect in their ability to generate TM 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 TM-cell generation in the absence of TRAF6. This treatment also increased CD8 TM cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/3ffb205f1ad6ab56e0528600a5eb2da8dece087c

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In Immunology

1. Erika L. Pearce
2. Rafi Ahmed
3. S. Kaech
4. E. Wherry
5. F. Sallusto
6. A. Lanzavecchia
7. Michael D. Buck
8. T. Malek

Citations in the corpus

• T cell metabolism drives immunity (2015, background): “Work from our laboratory has shown that CD8 memory T cells are dependent on FAO for their development, long-term persistence, and ability to robustly respond to antigen stimulation (Fig. 1; Pearce et al., 2009; van der Windt et al., 2012, 2013).”
• Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “We previously demonstrated that mitochondrial FAO stimulated downstream of TNF (tumor necrosis factor) receptor–associated factor 6 (TRAF6) is required for memory CD8 Tcell development (17).”
• Mitochondria in the regulation of innate and adaptive immunity (2015, positive): “Tm cells display increased mitochondrial number and spare respiratory capacity, which is fueled by fatty-acid oxidation to generate copious amount of ATP (Pearce et al., 2009; van der Windt et al., 2012).”
• Mitochondrial Respiratory Capacity Is A Critical Regulator Of CD8+ T Cell Memory Development (2011, methodology): “Previously we demonstrated that pharmacological modulation of fatty acid oxidation (FAO) enhanced CD8 memory T cell development after vaccination (Pearce et al., 2009).”
• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, background): “Lipid metabolism, including fatty acid and cholesterol metabolism, can affect CD8 + T cell activity and is involved in the regulation of T cell immunity induced by cancer immunotherapy (Ma et al., 2019; Pearce et al., 2009; Yang et al., 2016a; Zhang et al., 2017).”
• Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, result): “These results complement our previous findings that metformin promotes FAO in memory T cells and enhances their development in vivo (Pearce et al., 2009).”
• Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. (2013, positive): “Conversely, enforcing FAO either by overexpressing carnitine palmitoyltransferase 1a (Cpt1a), a rate-limiting enzyme in FAO (22), or by inhibiting activity of the mammalian target of rapamycin (mTOR) resulted in increased numbers of memory CD8 + T cells (21, 23).”
• Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, background): “In contrast, a TNFR pathway is required for the initiation of mitochondrial FAO and T cell memory development (Pearce et al., 2009).”