Increased mammalian target of rapamycin complex 2 signaling promotes age-related decline in CD4 T cell signaling and function

Journal of Immunology

Volumn 191, Issue 9, 2013, Pages 4648-4655

  Perkey, Eric ^a   Fingar, Diane ^b   Miller, Richard A ^b,c   Garcia, Gonzalo G ^b  

^a UNIVERSITY OF MICHIGAN   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; RHEB PROTEIN; T LYMPHOCYTE RECEPTOR; CARRIER PROTEIN; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MONOMERIC GUANINE NUCLEOTIDE BINDING PROTEIN; MULTIPROTEIN COMPLEX; NEUROPEPTIDE; RAPAMYCIN; RHEB PROTEIN, MOUSE; STRESS-ACTIVATED PROTEIN KINASE-INTERACTING PROTEIN, MOUSE; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2;

AGING; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CD4+ T LYMPHOCYTE; CONTROLLED STUDY; FEMALE; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SIGNALING; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; T LYMPHOCYTE ACTIVATION; UPREGULATION; ANIMAL; BAGG ALBINO MOUSE; BIOSYNTHESIS; C57BL MOUSE; CELL CULTURE; DRUG EFFECTS; GENETICS; IMMUNOLOGY; KNOCKOUT MOUSE; METABOLISM; SIGNAL TRANSDUCTION;

AGING; ANIMALS; CARRIER PROTEINS; CD4-POSITIVE T-LYMPHOCYTES; CELLS, CULTURED; MICE; MICE, INBRED BALB C; MICE, INBRED C57BL; MICE, KNOCKOUT; MONOMERIC GTP-BINDING PROTEINS; MULTIPROTEIN COMPLEXES; NEUROPEPTIDES; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84885994719     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1300750     Document Type: Article

References (69)

1. Evans, D. S., P. Kapahi, W.-C. Hsueh, and L. Kockel. 2011. TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing Res. Rev. 10: 225-237.
2. Robida-Stubbs, S., K. Glover-Cutter, D. W. Lamming, M. Mizunuma, S. D. Narasimhan, E. Neumann-Haefelin, D. M. Sabatini, and T. K. Blackwell. 2012. TOR signaling and rapamycin influence longevity by regulating SKN-1/ Nrf and DAF-16/FoxO. Cell Metab. 15: 713-724.
3. Zoncu, R., A. Efeyan, and D. M. Sabatini. 2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12: 21-35.
4. Harrison, D. E., R. Strong, Z. D. Sharp, J. F. Nelson, C. M. Astle, K. Flurkey, N. L. Nadon, J. E. Wilkinson, K. Frenkel, C. S. Carter, et al 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460: 392-395.
5. Proud, C. G. 2007. Amino acids and mTOR signalling in anabolic function. Biochem. Soc. Trans. 35: 1187-1190.
6. Manning, B. D., and L. C. Cantley. 2003. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28: 573-576.
7. Saucedo, L. J., X. Gao, D. A. Chiarelli, L. Li, D. Pan, and B. A. Edgar. 2003. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5: 566-571.
8. Garami, A., F. J. T. Zwartkruis, T. Nobukuni, M. Joaquin, M. Roccio, H. Stocker, S. C. Kozma, E. Hafen, J. L. Bos, and G. Thomas. 2003. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11: 1457-1466.
9. Magnuson, B., B. Ekim, and D. C. Fingar. 2012. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem. J. 441: 1-21.
10. O'Brien, T. F., B. K. Gorentla, D. Xie, S. Srivatsan, I. X. McLeod, Y.-W. He, and X.-P. Zhong. 2011. Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur. J. Immunol. 41: 3361-3370.
11. Waickman, A. T., and J. D. Powell. 2012. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249: 43-58.
12. Waickman, A. T., and J. D. Powell. 2012. Mammalian target of rapamycin integrates diverse inputs to guide the outcome of antigen recognition in T cells. J. Immunol. 188: 4721-4729.
13. Fadri, M., A. Daquinag, S. Wang, T. Xue, and J. Kunz. 2005. The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5- bisphosphate and TORC2. Mol. Biol. Cell 16: 1883-1900.
14. Gu, Y., J. Lindner, A. Kumar, W. Yuan, and M. A. Magnuson. 2011. Rictor/ mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 60: 827-837.
15. Saci, A., L. C. Cantley, and C. L. Carpenter. 2011. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol. Cell 42: 50-61.
16. Liu, L., S. Das, W. Losert, and C. A. Parent. 2010. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19: 845-857.
17. Ikenoue, T., K. Inoki, Q. Yang, X. Zhou, and K.-L. Guan. 2008. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27: 1919-1931.
18. Faure, S., L. I. Salazar-Fontana, M. Semichon, V. L. J. Tybulewicz, G. Bismuth, A. Trautmann, R. N. Germain, and J. Delon. 2004. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat. Immunol. 5: 272-279.
19. Gupta, M., A. E. W. Hendrickson, S. S. Yun, J. J. Han, P. A. Schneider, B. D. Koh, M. J. Stenson, L. E. Wellik, J. C. Shing, K. L. Peterson, et al 2012. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Blood 119: 476-487.
20. Goncharova, E. A., D. A. Goncharov, H. Li, W. Pimtong, S. Lu, I. Khavin, and V. P. Krymskaya. 2011. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol. Cell. Biol. 31: 2484-2498.
21. Jacinto, E., V. Facchinetti, D. Liu, N. Soto, S. Wei, S. Y. Jung, Q. Huang, J. Qin, and B. Su. 2006. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127: 125-137.
22. Cybulski, N., and M. N. Hall. 2009. TOR complex 2: a signaling pathway of its own. Trends Biochem. Sci. 34: 620-627.
23. Miller, R. A., S. B. Berger, D. T. Burke, A. Galecki, G. G. Garcia, J. M. Harper, and A. A. Sadighi Akha. 2005. T cells in aging mice: genetic, developmental, and biochemical analyses. Immunol. Rev. 205: 94-103.
24. Haynes, L., and A. C. Maue. 2009. Effects of aging on T cell function. Curr. Opin. Immunol. 21: 414-417.
25. Garcia, G. G., and R. A. Miller. 1997. Differential tyrosine phosphorylation of zeta chain dimers in mouse CD4 T lymphocytes: effect of age. Cell. Immunol. 175: 51-57.
26. Garcia, G. G., and R. A. Miller. 2001. Single-cell analyses reveal two defects in peptidespecific activation of naive T cells from aged mice. J. Immunol. 166: 3151-3157.
27. Garcia, G. G., and R. A. Miller. 2002. Age-dependent defects in TCR-triggered cytoskeletal rearrangement in CD4+ T cells. J. Immunol. 169:5021-5027.
28. Garcia, G. G., and R. A. Miller. 2009. Age-related changes in lck-Vav signaling pathways in mouse CD4 T cells. Cell. Immunol. 259: 100-104.
29. Garcia, G. G., and R. A. Miller. 2011. Age-related defects in the cytoskeleton signaling pathways of CD4 T cells. Ageing Res. Rev. 10: 26-34.
30. Garcia, G. G., A. A. Sadighi Akha, and R. A. Miller. 2007. Age-related defects in moesin/ezrin cytoskeletal signals in mouse CD4 T cells. J. Immunol. 179: 6403-6409.
31. Garcia, G. G., and R. A. Miller. 2011. Ex vivo enzymatic treatment of aged CD4 T cells restores antigen-driven CD69 expression and proliferation in mice. Immunobiology 216: 66-71.
32. Perkey, E., R. A. Miller, and G. G. Garcia. 2012. Ex vivo enzymatic treatment of aged CD4 T cells restores cognate T cell helper function and enhances antibody production in mice. J. Immunol. 189: 5582-5589.
33. Tsukamoto, H., G. E. Huston, J. Dibble, D. K. Duso, and S. L. Swain. 2010. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185: 4535-4544.
34. Miller, R. A., D. E. Harrison, C. M. Astle, J. A. Baur, A. R. Boyd, R. de Cabo, E. Fernandez, K. Flurkey, M. A. Javors, J. F. Nelson, et al 2011. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66: 191-201.
35. Yin, J., Z. Ma, N. Selliah, D. K. Shivers, R. Q. Cron, and T. H. Finkel. 2006. Effective gene suppression using small interfering RNA in hard-to-transfect human T cells. J. Immunol. Methods 312: 1-11.
36. Haag, J., R. Voigt, S. Soeder, and T. Aigner. 2009. Efficient non-viral transfection of primary human adult chondrocytes in a high-throughput format. Osteoarthritis Cartilage. 17: 813-817.
37. Katewa, S. D., and P. Kapahi. 2011. Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp. Gerontol. 46: 382-390.
38. Sengupta, S., T. R. Peterson, M. Laplante, S. Oh, and D. M. Sabatini. 2010. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468: 1100-1104.
39. Lamming, D. W., L. Ye, P. Katajisto, M. D. Goncalves, M. Saitoh, D. M. Stevens, J. G. Davis, A. B. Salmon, A. Richardson, R. S. Ahima, et al 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335: 1638-1643.
40. Watson, A. R. O., and W. T. Lee. 2004. Differences in signaling molecule organization between naive and memory CD4+ T lymphocytes. J. Immunol. 173: 33-41.
41. Araki, K., A. H. Ellebedy, and R. Ahmed. 2011. TOR in the immune system. Curr. Opin. Cell Biol. 23: 707-715.
42. Huang, J., and B. D. Manning. 2009. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem. Soc. Trans. 37: 217-222.
43. García-Martínez, J. M., and D. R. Alessi. 2008. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416: 375-385.
44. Yang, Q., K. Inoki, T. Ikenoue, and K. L. Guan. 2006. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20: 2820-2832.
45. Haynes, L., and S. L. Swain. 2006. Why aging T cells fail: implications for vaccination. Immunity 24: 663-666.
46. Sadighi Akha, A. A., and R. A. Miller. 2005. Signal transduction in the aging immune system. Curr. Opin. Immunol. 17: 486-491.
47. Simpson, T. R., S. A. Quezada, and J. P. Allison. 2010. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr. Opin. Immunol. 22: 326-332.
48. Larbi, A., G. Pawelec, S. C. Wong, D. Goldeck, J. J.-Y. Tai, and T. Fulop. 2011. Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res. Rev. 10: 370-378.
49. Gough, N. R. 2012. Focus issue: TOR signaling, a tale of two complexes. Sci. Signal. 5: eg4.
50. Zhang, S., J. A. Readinger, W. DuBois, M. Janka-Junttila, R. Robinson, M. Pruitt, V. Bliskovsky, J. Z. Wu, K. Sakakibara, J. Patel, et al. 2011. Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood 117: 1228-1238.
51. Yu, M., G. Li, W.-W. Lee, M. Yuan, D. Cui, C. M. Weyand, and J. J. Goronzy. 2012. Signal inhibition by the dual-specific phosphatase 4 impairs T celldependent B-cell responses with age. Proc. Natl. Acad. Sci. USA 109: E879-E888.
52. Ohne, Y., T. Takahara, and T. Maeda. 2009. Evaluation of mTOR function by a gain-of-function approach. Cell Cycle 8: 573-579.
53. Lionello, M., S. Blandamura, L. Loreggian, G. Ottaviano, L. Giacomelli, R. Marchese-Ragona, C. Velardita, A. Staffieri, and G. Marioni. 2012. High mTOR expression is associated with a worse oncological outcome in laryngeal carcinoma treated with postoperative radiotherapy: a pilot study. J. Oral Pathol. Med. 41: 136-140.
54. O'Brien, T. F., and X.-P. Zhong. 2012. The role and regulation of mTOR in Tlymphocyte function. Arch. Immunol. Ther. Exp. (Warsz.) 60: 173-181.
55. Neff, F., D. Flores-Dominguez, D. P. Ryan, M. Horsch, S. Schröder, T. Adler, L. C. Afonso, J. A. Aguilar-Pimentel, L. Becker, L. Garrett, et al 2013. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123: 3272-3291.
56. Ferrer, I. R., M. E. Wagener, J. M. Robertson, A. P. Turner, K. Araki, R. Ahmed, A. D. Kirk, C. P. Larsen, and M. L. Ford. 2010. Cutting edge: Rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses. J. Immunol. 185: 2004-2008.
57. Saemann, M. D., M. Haidinger, M. Hecking, W. H. Horl, and T. Weichhart. 2009. The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am. J. Transplant. 9: 2655-2661.
58. Jagannath, C., D. R. Lindsey, S. Dhandayuthapani, Y. Xu, R. L. Hunter, Jr., and N. T. Eissa. 2009. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat. Med. 15: 267-276.
59. Ohkusu, K., J. Du, K. I. Isobe, H. Yi, A. A. Akhand, M. Kato, H. Suzuki, H. Hidaka, and I. Nakashima. 1997. Protein kinase C alpha-mediated chronic signal transduction for immunosenescence. J. Immunol. 159: 2082-2084.
60. Fernández-Gutiérrez, B., J. A. Jover, S. De Miguel, C. Hernández-García, M. T. Vidán, J. M. Ribera, A. Bañares, and J. A. Serra. 1999. Early lymphocyte activation in elderly humans: impaired T and T-dependent B cell responses. Exp. Gerontol. 34: 217-229.
61. Das, F., N. Ghosh-Choudhury, N. Dey, C. C. Mandal, L. Mahimainathan, B. S. Kasinath, H. E. Abboud, and G. G. Choudhury. 2012. Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase. J. Biol. Chem. 287: 3808-3822.
62. El-Naggar, S., Y. Liu, and D. C. Dean. 2009. Mutation of the Rb1 pathway leads to overexpression of mTor, constitutive phosphorylation of Akt on serine 473, resistance to anoikis, and a block in c-Raf activation. Mol. Cell. Biol. 29: 5710-5717.
63. Haynes, L., and S. M. Eaton. 2005. The effect of age on the cognate function of CD4+ T cells. Immunol. Rev. 205: 220-228.
64. Haynes, L., S. M. Eaton, E. M. Burns, T. D. Randall, and S. L. Swain. 2003. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc. Natl. Acad. Sci. USA 100: 15053-15058.
65. Sasaki, A. T., and R. A. Firtel. 2006. Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR. Eur. J. Cell Biol. 85: 873-895.
66. Weng, N.-P., A. N. Akbar, and J. Goronzy. 2009. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 30: 306-312.
67. Boulbes, D., C. H. Chen, T. Shaikenov, N. K. Agarwal, T. R. Peterson, T. A. Addona, H. Keshishian, S. A. Carr, M. A. Magnuson, D. M. Sabatini, and D. Sarbassov. 2010. Rictor phosphorylation on the Thr-1135 site does not require mammalian target of rapamycin complex 2. Mol. Cancer Res. 8: 896-906.
68. Agarwal, N. K., C. H. Chen, H. Cho, D. R. Boulbès, E. Spooner, and D. D. Sarbassov. 2013. Rictor regulates cell migration by suppressing RhoGDI2. Oncogene 32: 2521-2526.
69. Schroder, W. A., M. Buck, N. Cloonan, J. F. Hancock, A. Suhrbier, T. Sculley, and G. Bushell. 2007. Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell. Signal. 19: 1279-1289.