IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 May 11

PMID 25957683

Citations 184

Authors

Guoliang Cui

Matthew M Staron

Simon M Gray

Ping-Chih Ho

Robert A Amezquita

JingXia Wu

Susan M Kaech

Affiliations

Soon will be listed here.

Abstract

Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.

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References

Rathmell J, Farkash E, Gao W, Thompson C . IL-7 enhances the survival and maintains the size of naive T cells. J Immunol. 2001; 167(12):6869-76. DOI: 10.4049/jimmunol.167.12.6869. View

Opferman J, Letai A, Beard C, Sorcinelli M, Ong C, Korsmeyer S . Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003; 426(6967):671-6. DOI: 10.1038/nature02067. View

Wofford J, Wieman H, Jacobs S, Zhao Y, Rathmell J . IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2007; 111(4):2101-11. PMC: 2234050. DOI: 10.1182/blood-2007-06-096297. View

Tan J, Ernst B, Kieper W, Leroy E, Sprent J, Surh C . Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002; 195(12):1523-32. PMC: 2193564. DOI: 10.1084/jem.20020066. View

Abrami L, Berthonaud V, Deen P, Rousselet G, Tacnet F, Ripoche P . Glycerol permeability of mutant aquaporin 1 and other AQP-MIP proteins: inhibition studies. Pflugers Arch. 1996; 431(3):408-14. DOI: 10.1007/BF02207279. View

Fox C, Hammerman P, Thompson C . Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol. 2005; 5(11):844-52. DOI: 10.1038/nri1710. View

Pellegrini M, Calzascia T, Toe J, Preston S, Lin A, Elford A . IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011; 144(4):601-13. DOI: 10.1016/j.cell.2011.01.011. View

Kieper W, Tan J, Bondi-Boyd B, Gapin L, Sprent J, Ceredig R . Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med. 2002; 195(12):1533-9. PMC: 2193553. DOI: 10.1084/jem.20020067. View

Schluns K, Kieper W, Jameson S, Lefrancois L . Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2001; 1(5):426-32. DOI: 10.1038/80868. View

10.

van der Windt G, Everts B, Chang C, Curtis J, Freitas T, Amiel E . Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2011; 36(1):68-78. PMC: 3269311. DOI: 10.1016/j.immuni.2011.12.007. View

11.

Barata J, Silva A, Brandao J, Nadler L, Cardoso A, Boussiotis V . Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med. 2004; 200(5):659-69. PMC: 2212738. DOI: 10.1084/jem.20040789. View

12.

Pearce E, Walsh M, Cejas P, Harms G, Shen H, Wang L . Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009; 460(7251):103-7. PMC: 2803086. DOI: 10.1038/nature08097. View

13.

Rodriguez A, Catalan V, Gomez-Ambrosi J, Fruhbeck G . Aquaglyceroporins serve as metabolic gateways in adiposity and insulin resistance control. Cell Cycle. 2011; 10(10):1548-56. PMC: 3127157. DOI: 10.4161/cc.10.10.15672. View

14.

OSullivan D, van der Windt G, Huang S, Curtis J, Chang C, Buck M . Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014; 41(1):75-88. PMC: 4120664. DOI: 10.1016/j.immuni.2014.06.005. View

15.

Beura L, Masopust D . SnapShot: resident memory T cells. Cell. 2014; 157(6):1488-1488.e1. DOI: 10.1016/j.cell.2014.05.026. View

16.

Swain S, Hu H, Huston G . Class II-independent generation of CD4 memory T cells from effectors. Science. 1999; 286(5443):1381-3. DOI: 10.1126/science.286.5443.1381. View

17.

Tanchot C, Lemonnier F, Perarnau B, Freitas A, Rocha B . Differential requirements for survival and proliferation of CD8 naïve or memory T cells. Science. 1997; 276(5321):2057-62. DOI: 10.1126/science.276.5321.2057. View

18.

Sportes C, Babb R, Krumlauf M, Hakim F, Steinberg S, Chow C . Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin Cancer Res. 2010; 16(2):727-35. PMC: 2808195. DOI: 10.1158/1078-0432.CCR-09-1303. View

19.

Goldrath A, Sivakumar P, Glaccum M, Kennedy M, Bevan M, Benoist C . Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med. 2002; 195(12):1515-22. PMC: 2193554. DOI: 10.1084/jem.20020033. View

20.

Pearson C, Silva A, Seddon B . Exogenous amino acids are essential for interleukin-7 induced CD8 T cell growth. [corrected]. PLoS One. 2012; 7(4):e33998. PMC: 3328464. DOI: 10.1371/journal.pone.0033998. View