Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice

Aging Cell

Volumn 14, Issue 6, 2015, Pages 945-956

  Hurez, Vincent ^a   Dao, Vinh ^a   Liu, Aijie ^a   Pandeswara, Srilakshmi ^a   Gelfond, Jonathan ^a   Sun, Lishi ^a   Bergman, Molly ^a   Orihuela, Carlos J ^a   Galvan, Veronica ^a,b   Padrón, Álvaro ^a   Drerup, Justin ^a   Liu, Yang ^a   Hasty, Paul ^a,b   Sharp, Zelton Dave ^a   Curiel, Tyler J ^a  

^a UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^b Mays Cancer Center at UT Health San Antonio   (United States)

Author keywords

Immune cell differentiation; Immunology; Longevity; Mammalian (mechanistic) target of rapamycin; Metagenomics; Microarray; Rapamycin; Transcriptomics

Indexed keywords

CHEMOKINE RECEPTOR CCR7; EUDRAGIT; FLAGELLIN; INTERLEUKIN 22; L SELECTIN; MAMMALIAN TARGET OF RAPAMYCIN; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN BCL 6; RAPAMYCIN; RETINOID RELATED ORPHAN RECEPTOR GAMMA; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR GATA 3; TRANSCRIPTION FACTOR T BET; ANTINEOPLASTIC ANTIBIOTIC; INTERLEUKIN DERIVATIVE; INTERLEUKIN-22; MTOR PROTEIN, MOUSE; PDCD1 PROTEIN, MOUSE; TARGET OF RAPAMYCIN KINASE;

ACIDOBACTERIA; AGED; AGING; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMICROBIAL ACTIVITY; ARTICLE; AUTOPHAGY; B LYMPHOCYTE; B LYMPHOCYTE DIFFERENTIATION; BACTEROIDETES; BONE MARROW CELL; CANCER SUSCEPTIBILITY; CD3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL AGING; CELL DEATH; CELL SUBPOPULATION; CITROBACTER RODENTIUM; CONTROLLED STUDY; DENDRITIC CELL; DRUG EFFECT; ENTEROBACTERIACEAE INFECTION; FEMALE; FIRMICUTES; GENE EXPRESSION PROFILING; HOMEOSTASIS; IMMUNE DEFICIENCY; IMMUNOCOMPETENT CELL; IMMUNOREGULATION; IN VITRO STUDY; IN VIVO STUDY; INFECTION; INFECTION SENSITIVITY; INFLAMMATION; INTESTINE FLORA; INTESTINE INFECTION; LIFE EXTENSION; LONG TERM CARE; LONGEVITY; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE MIGRATION; LYMPHOCYTE SUBPOPULATION; LYMPHOID CELL; MALE; MELANOMA; METAGENOME; METAGENOMICS; MOUSE; NEOPLASM; NONHUMAN; PEYER PATCH; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; SPLEEN CELL; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TH0 CELL; TH1 CELL; TH17 CELL; TH2 CELL; TH22 CELL; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; C57BL MOUSE; CELL DIFFERENTIATION; CYTOLOGY; DRUG EFFECTS; EXPERIMENTAL MELANOMA; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; METABOLISM; SPLEEN;

AGING; ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; B-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; DENDRITIC CELLS; FEMALE; FLAGELLIN; GASTROINTESTINAL MICROBIOME; GENE EXPRESSION PROFILING; IMMUNOLOGIC MEMORY; INTERLEUKINS; LONGEVITY; MALE; MELANOMA, EXPERIMENTAL; MICE; MICE, INBRED C57BL; MYELOID CELLS; PROGRAMMED CELL DEATH 1 RECEPTOR; SIROLIMUS; SPLEEN; T-LYMPHOCYTES, REGULATORY; TOR SERINE-THREONINE KINASES;

EID: 84954361691     PISSN: 14749718     EISSN: 14749726     Source Type: Journal    
DOI: 10.1111/acel.12380     Document Type: Article

References (53)

1. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108-112.
2. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687.
3. Basu R, O'Quinn DB, Silberger DJ, Schoeb TR, Fouser L, Ouyang W, Hatton RD, Weaver CT (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061-1075.
4. Chen C, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75.
5. Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325-338.
6. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401.
7. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5, 3557.
8. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295-303.
9. Diken M, Kreiter S, Vascotto F, Selmi A, Attig S, Diekmann J, Huber C, Tureci O, Sahin U (2013) mTOR Inhibition Improves Antitumor Effects of Vaccination with Antigen-Encoding RNA. Cancer Immunol. Res. 1, 386-392.
10. Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, Kozma SC, Thomas G, Sonenberg N (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328, 1172-1176.
11. Ferrer IR, Wagener ME, Robertson JM, Turner AP, Araki K, Ahmed R, Kirk AD, Larsen CP, Ford ML (2010) Cutting edge: Rapamycin augments pathogen-specific but not graft-reactive CD8 + T cell responses. J. Immunol. 185, 2004-2008.
12. Fielhaber JA, Carroll SF, Dydensborg AB, Shourian M, Triantafillopoulos A, Harel S, Hussain SN, Bouchard M, Qureshi ST, Kristof AS (2012) Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. J. Immunol. 188, 4535-4542.
13. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69(Suppl 1), S4-S9.
14. Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Zugich J (2015) Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130-138.
15. Golovina TN, Mikheeva T, Brusko TM, Blazar BR, Bluestone JA, Riley JL (2011) Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. PLoS ONE 6, e15868.
16. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392-395.
17. Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD (2014) eRapa Restores a Normal Life Span in a FAP Mouse Model. Cancer Prev. Res. (Phila.) 7, 169-178.
18. Hazenberg MD, Spits H (2014) Human innate lymphoid cells. Blood 124, 700-709.
19. Hurez V, Daniel BJ, Sun L, Liu AJ, Ludwig SM, Kious MJ, Thibodeaux SR, Pandeswara S, Murthy K, Livi CB, Wall S, Brumlik MJ, Shin T, Zhang B, Curiel TJ (2012) Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. Cancer Res. 72, 2089-2099.
20. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327, 291-295.
21. Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi H, Doherty PC, Thomas PG, McGargill MA (2013) The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat. Immunol. 14, 1266-1276.
22. Kinnebrew MA, Buffie CG, Diehl GE, Zenewicz LA, Leiner I, Hohl TM, Flavell RA, Littman DR, Pamer EG (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276-287.
23. Kopf H, de la Rosa GM, Howard OM, Chen X (2007) Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3 + T regulatory cells. Int. Immunopharmacol. 7, 1819-1824.
24. Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C (2010) Partial restoration of T cell function in aged mice by in vitro blockade of the PD-1/PD-L1 pathway. Aging Cell 9, 785-798.
25. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638-1643.
26. Lamming DW, Ye L, Sabatini DM, Baur JA (2013) Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980-989.
27. Laplante M, Sabatini DM (2012) mTOR Signaling in Growth Control and Disease. Cell 149, 274-293.
28. Leontieva OV, Paszkiewicz GM, Blagosklonny MV (2014) Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell 13, 616-622.
29. Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD (2013) Rapamycin extends life span of Rb1 + /- mice by inhibiting neuroendocrine tumors. Aging (Albany NY) 5, 100-110.
30. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB (2014) mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179.
31. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191-201.
32. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13, 468-477.
33. Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16-25.
34. Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schroder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Holter SM, Moreth K, Prehn C, Puk O, Racz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Hofler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D (2013) Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123, 3272-3291.
35. Powell JD, Pollizzi KN, Heikamp EB, Horton MR (2012) Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39-68.
36. Rodriguez KA, Dodds SG, Strong R, Galvan V, Sharp ZD, Buffenstein R (2014) Divergent tissue and sex effects of rapamycin on the proteasome-chaperone network of old mice. Front. Mol. Neurosci. 7, 83.
37. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144.
38. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100-1104.
39. Shi Y, August DA (2008) A new trick for an old drug: mTOR inhibitor rapamycin augments the effect of fluorouracil on hepatocellular carcinoma by inducing cell senescence. Cancer Biol. Ther. 7, 397-398.
40. Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155-162.
41. Sinclair LV, Finlay D, Feijoo C, Cornish GH, Gray A, Ager A, Okkenhaug K, Hagenbeek TJ, Spits H, Cantrell DA (2008) Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513-521.
42. Sofroniadou S, Goldsmith D (2011) Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects. Drug Saf. 34, 97-115.
43. Sonnenberg GF, Artis D (2012) Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601-610.
44. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells-a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145-149.
45. Sun L, Hurez VJ, Thibodeaux SR, Kious MJ, Liu A, Lin P, Murthy K, Pandeswara S, Shin T, Curiel TJ (2012) Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells. Aging Cell 11, 509-519.
46. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM (2012) A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109-113.
47. Wander SA, Hennessy BT, Slingerland JM (2011) Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest. 121, 1231-1241.
48. Weichhart T, Saemann MD (2009) The multiple facets of mTOR in immunity. Trends Immunol. 30, 218-226.
49. Wherry EJ (2011) T cell exhaustion. Nat. Immunol. 12, 492-499.
50. Xu X, Ye L, Araki K, Ahmed R (2012) mTOR, linking metabolism and immunity. Semin. Immunol. 24, 429-435.
51. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942-946.
52. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499, 485-490.
53. Zhang Y, Bokov A, Gelfond J, Soto V, Ikeno Y, Hubbard G, Diaz V, Sloane L, Maslin K, Treaster S, Rendon S, van Remmen H, Ward W, Javors M, Richardson A, Austad SN, Fischer K (2014) Rapamycin extends life and health in C57BL/6 mice. J. Gerontol. A Biol. Sci. Med. Sci. 69, 119-130.