mTOR signaling in the differentiation and function of regulatory and effector T cells

Current Opinion in Immunology

Volumn 46, Issue , 2017, Pages 103-111

  Zeng, Hu ^a   Chi, Hongbo ^a  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; TARGET OF RAPAMYCIN KINASE;

CELL METABOLISM; EFFECTOR CELL; HUMAN; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; T LYMPHOCYTE SUBPOPULATION; ANIMAL; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CYTOLOGY; HELPER CELL; IMMUNOLOGY; IMMUNOMODULATION; LYMPHOCYTE ACTIVATION; METABOLISM;

ANIMALS; CD8-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; HUMANS; IMMUNOMODULATION; LYMPHOCYTE ACTIVATION; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 2; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, HELPER-INDUCER; T-LYMPHOCYTES, REGULATORY; TOR SERINE-THREONINE KINASES;

EID: 85019387949     PISSN: 09527915     EISSN: 18790372     Source Type: Journal    
DOI: 10.1016/j.coi.2017.04.005     Document Type: Review

References (68)

1. 1 Saxton, R.A., Sabatini, D.M., mTOR signaling in growth, metabolism, and disease. Cell 169 (2017), 361–371.
2. 2 Chi, H., Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12 (2012), 325–338.
3. 3 Zeng, H., Chi, H., Metabolic control of regulatory T cell development and function. Trends Immunol. 36 (2015), 3–12.
4. 4 Chapman, N.M., Chi, H., mTOR links environmental signals to T cell fate decisions. Front. Immunol., 5, 2014, 686.
5. 5 Zeng, H., Yang, K., Cloer, C., Neale, G., Vogel, P., Chi, H., mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499 (2013), 485–490.
6. 6 De Rosa, V., Galgani, M., Porcellini, A., Colamatteo, A., Santopaolo, M., Zuchegna, C., Romano, A., De Simone, S., Procaccini, C., La Rocca, C., et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 16 (2015), 1174–1184.
7. 7 Park, Y., Jin, H.S., Lopez, J., Elly, C., Kim, G., Murai, M., Kronenberg, M., Liu, Y.C., TSC1 regulates the balance between effector and regulatory T cells. J. Clin. Invest. 123 (2013), 5165–5178.
8. 8 Yang, K., Neale, G., Green, D.R., He, W., Chi, H., The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12 (2011), 888–897.
9. 9 O'Brien, T.F., Gorentla, B.K., Xie, D., Srivatsan, S., McLeod, I.X., He, Y.W., Zhong, X.P., Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur. J. Immunol. 41 (2011), 3361–3370.
10. 10 Wu, Q., Liu, Y., Chen, C., Ikenoue, T., Qiao, Y., Li, C.S., Li, W., Guan, K.L., Liu, Y., Zheng, P., The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. J. Immunol. 187 (2011), 1106–1112.
11. 11 Chen, H., Zhang, L., Zhang, H., Xiao, Y., Shao, L., Li, H., Yin, H., Wang, R., Liu, G., Corley, D., et al. Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+ CD25+ Foxp3+ regulatory T-cell development in mice. FASEB J. 27 (2013), 3979–3990.
12. 12•• Shrestha, S., Yang, K., Guy, C., Vogel, P., Neale, G., Chi, H., Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16 (2015), 178–187 Ref. [12••] revealed that excessive activation of mTORC2 disrupts Treg stability and impairs their ability to specifically suppress Th1 and Tfh cells.
13. 13•• Huynh, A., DuPage, M., Priyadharshini, B., Sage, P.T., Quiros, J., Borges, C.M., Townamchai, N., Gerriets, V.A., Rathmell, J.C., Sharpe, A.H., et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16 (2015), 188–196 Ref. [13••] revealed that excessive activation of mTORC2 disrupts Treg stability and impairs their ability to specifically suppress Th1 and Tfh cells.
14. 14 Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X.P., Forbush, K., Rudensky, A.Y., Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463 (2010), 808–812.
15. 15 Ohkura, N., Hamaguchi, M., Morikawa, H., Sugimura, K., Tanaka, A., Ito, Y., Osaki, M., Tanaka, Y., Yamashita, R., Nakano, N., et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37 (2012), 785–799.
16. 16 Delgoffe, G.M., Kole, T.P., Zheng, Y., Zarek, P.E., Matthews, K.L., Xiao, B., Worley, P.F., Kozma, S.C., Powell, J.D., The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30 (2009), 832–844.
17. 17 Delgoffe, G.M., Pollizzi, K.N., Waickman, A.T., Heikamp, E., Meyers, D.J., Horton, M.R., Xiao, B., Worley, P.F., Powell, J.D., The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12 (2011), 295–303.
18. 18 Lee, K., Gudapati, P., Dragovic, S., Spencer, C., Joyce, S., Killeen, N., Magnuson, M.A., Boothby, M., Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32 (2010), 743–753.
19. 19 Yang, K., Shrestha, S., Zeng, H., Karmaus, P.W., Neale, G., Vogel, P., Guertin, D.A., Lamb, R.F., Chi, H., T cell exit from quiescence and differentiation into Th2 cells depend on raptor-mTORC1-mediated metabolic reprogramming. Immunity 39 (2013), 1043–1056.
20. 20 Kurebayashi, Y., Nagai, S., Ikejiri, A., Ohtani, M., Ichiyama, K., Baba, Y., Yamada, T., Egami, S., Hoshii, T., Hirao, A., et al. PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. Cell Rep. 1 (2012), 360–373.
21. 21 Ray, J.P., Staron, M.M., Shyer, J.A., Ho, P.C., Marshall, H.D., Gray, S.M., Laidlaw, B.J., Araki, K., Ahmed, R., Kaech, S.M., et al. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43 (2015), 690–702.
22. 22• Ramiscal, R.R., Parish, I.A., Lee-Young, R.S., Babon, J.J., Blagih, J., Pratama, A., Martin, J., Hawley, N., Cappello, J.Y., Nieto, P.F., et al. Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. Elife, 4, 2015, e08698 Ref. [22•] showed that mTOR signaling promotes Tfh differentiation and function, while Ref. [21•] revealed that silencing of mTORC1 increases Tfh generation, but preserves their function.
23. 23• Zeng, H., Cohen, S., Guy, C., Shrestha, S., Neale, G., Brown, S.A., Cloer, C., Kishton, R.J., Gao, X., Youngblood, B., et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45 (2016), 540–554 Ref. [23•] showed that mTOR signaling promotes Tfh differentiation and function, while Ref. [21•] revealed that silencing of mTORC1 increases Tfh generation, but preserves their function.
24. 24• Yang, J., Lin, X., Pan, Y., Wang, J., Chen, P., Huang, H., Xue, H.H., Gao, J., Zhong, X.P., Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses. Elife, 5, 2016 Ref. [24•] showed that mTOR signaling promotes Tfh differentiation and function, while Ref. [21•] revealed that silencing of mTORC1 increases Tfh generation, but preserves their function.
25. 25 Rolf, J., Bell, S.E., Kovesdi, D., Janas, M.L., Soond, D.R., Webb, L.M., Santinelli, S., Saunders, T., Hebeis, B., Killeen, N., et al. Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol. 185 (2010), 4042–4052.
26. 26 Tan, H., Yang, K., Li, Y., Shaw, T.I., Wang, Y., Blanco, D.B., Wang, X., Cho, J.H., Wang, H., Rankin, S., et al. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity 46 (2017), 488–503.
27. 27 Choi, Y.S., Gullicksrud, J.A., Xing, S., Zeng, Z., Shan, Q., Li, F., Love, P.E., Peng, W., Xue, H.H., Crotty, S., LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol. 16 (2015), 980–990.
28. 28 Xu, L., Cao, Y., Xie, Z., Huang, Q., Bai, Q., Yang, X., He, R., Hao, Y., Wang, H., Zhao, T., et al. The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nat. Immunol. 16 (2015), 991–999.
29. 29 Daley, S.R., Coakley, K.M., Hu, D.Y., Randall, K.L., Jenne, C.N., Limnander, A., Myers, D.R., Polakos, N.K., Enders, A., Roots, C., et al. Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios(+) T cells and autoantibodies. Elife, 2, 2013, e01020.
30. 30 Rao, R.R., Li, Q., Odunsi, K., Shrikant, P.A., The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32 (2010), 67–78.
31. + T cell formation with elevated recall response.
32. 32 Krishna, S., Yang, J., Wang, H., Qiu, Y., Zhong, X.P., Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection. Infect. Immun. 82 (2014), 3045–3057.
33. 33 Araki, K., Turner, A.P., Shaffer, V.O., Gangappa, S., Keller, S.A., Bachmann, M.F., Larsen, C.P., Ahmed, R., mTOR regulates memory CD8 T-cell differentiation. Nature 460 (2009), 108–112.
34. 34 Pearce, E.L., Walsh, M.C., Cejas, P.J., Harms, G.M., Shen, H., Wang, L.S., Jones, R.G., Choi, Y., Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460 (2009), 103–107.
35. 35 Shrestha, S., Yang, K., Wei, J., Karmaus, P.W., Neale, G., Chi, H., Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 14858–14863.
36. 36 van der Windt, G.J., Everts, B., Chang, C.H., Curtis, J.D., Freitas, T.C., Amiel, E., Pearce, E.J., Pearce, E.L., Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36 (2012), 68–78.
37. + T cell generation and function through a Foxo1-dependent mechanism.
38. 38 Liu, G., Yang, K., Burns, S., Shrestha, S., Chi, H., The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat. Immunol. 11 (2010), 1047–1056.
39. 39 Liu, G., Burns, S., Huang, G., Boyd, K., Proia, R.L., Flavell, R.A., Chi, H., The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat. Immunol. 10 (2009), 769–777.
40. 40 Weiss, J.M., Bilate, A.M., Gobert, M., Ding, Y., Curotto de Lafaille, M.A., Parkhurst, C.N., Xiong, H., Dolpady, J., Frey, A.B., Ruocco, M.G., et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209 (2012), 1723–1742 S1721.
41. 41 Yadav, M., Louvet, C., Davini, D., Gardner, J.M., Martinez-Llordella, M., Bailey-Bucktrout, S., Anthony, B.A., Sverdrup, F.M., Head, R., Kuster, D.J., et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209 (2012), 1713–1722 S1711–1719.
42. 42 Delgoffe, G.M., Woo, S.R., Turnis, M.E., Gravano, D.M., Guy, C., Overacre, A.E., Bettini, M.L., Vogel, P., Finkelstein, D., Bonnevier, J., et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501 (2013), 252–256.
43. 43 Hansen, W., Hutzler, M., Abel, S., Alter, C., Stockmann, C., Kliche, S., Albert, J., Sparwasser, T., Sakaguchi, S., Westendorf, A.M., et al. Neuropilin 1 deficiency on CD4 + Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med. 209 (2012), 2001–2016.
44. 44• Gerriets, V.A., Kishton, R.J., Johnson, M.O., Cohen, S., Siska, P.J., Nichols, A.G., Warmoes, M.O., de Cubas, A.A., MacIver, N.J., Locasale, J.W., et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17 (2016), 1459–1466 Ref [44•] revealed that mTORC1 is positively and negatively regulated by TLR1/2 and FOXP3, respectively. TLR1/2 signaling promotes Treg proliferation, but impairs Treg suppressive activity. In contrast, FOXP3 expression inhibits mTORC1 activation and glycolysis, and promotes mitochondrial oxidative phosphorylation.
45. 45 Chen, L.C., Nicholson, Y.T., Rosborough, B.R., Thomson, A.W., Raimondi, G., A novel mTORC1-dependent, Akt-independent pathway differentiates the gut tropism of regulatory and conventional CD4 T cells. J. Immunol. 197 (2016), 1137–1147.
46. 46 Wei, J., Long, L., Yang, K., Guy, C., Shrestha, S., Chen, Z., Wu, C., Vogel, P., Neale, G., Green, D.R., et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17 (2016), 277–285.
47. 47 Kabat, A.M., Harrison, O.J., Riffelmacher, T., Moghaddam, A.E., Pearson, C.F., Laing, A., Abeler-Dorner, L., Forman, S.P., Grencis, R.K., Sattentau, Q., et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. Elife, 5, 2016, e12444.
48. 48 Apostolidis, S.A., Rodriguez-Rodriguez, N., Suarez-Fueyo, A., Dioufa, N., Ozcan, E., Crispin, J.C., Tsokos, M.G., Tsokos, G.C., Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17 (2016), 556–564.
49. 49 Muljo, S.A., Ansel, K.M., Kanellopoulou, C., Livingston, D.M., Rao, A., Rajewsky, K., Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202 (2005), 261–269.
50. 50 Cobb, B.S., Hertweck, A., Smith, J., O'Connor, E., Graf, D., Cook, T., Smale, S.T., Sakaguchi, S., Livesey, F.J., Fisher, A.G., et al. A role for Dicer in immune regulation. J. Exp. Med. 203 (2006), 2519–2527.
51. 51 Chong, M.M., Rasmussen, J.P., Rudensky, A.Y., Littman, D.R., The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205 (2008), 2005–2017.
52. 52 Warth, S.C., Hoefig, K.P., Hiekel, A., Schallenberg, S., Jovanovic, K., Klein, L., Kretschmer, K., Ansel, K.M., Heissmeyer, V., Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. EMBO J. 34 (2015), 1195–1213.
53. 53 Singh, Y., Garden, O.A., Lang, F., Cobb, B.S., MicroRNA-15b/16 enhances the induction of regulatory T cells by regulating the expression of rictor and mTOR. J. Immunol. 195 (2015), 5667–5677.
54. 54 Nakaya, M., Xiao, Y., Zhou, X., Chang, J.H., Chang, M., Cheng, X., Blonska, M., Lin, X., Sun, S.C., Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40 (2014), 692–705.
55. 55 Hamilton, K.S., Phong, B., Corey, C., Cheng, J., Gorentla, B., Zhong, X., Shiva, S., Kane, L.P., T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci. Signal., 7, 2014, ra55.
56. 56 Li, P., Spolski, R., Liao, W., Leonard, W.J., Complex interactions of transcription factors in mediating cytokine biology in T cells. Immunol. Rev. 261 (2014), 141–156.
57. 57 Chang, H.C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G.L., Jabeen, R., McKinley, C., Ahyi, A.N., Han, L., et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11 (2010), 527–534.
58. 58 Licona-Limon, P., Henao-Mejia, J., Temann, A.U., Gagliani, N., Licona-Limon, I., Ishigame, H., Hao, L., Herbert, D.R., Flavell, R.A., Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39 (2013), 744–757.
59. 59 Wang, Y., Bi, Y., Chen, X., Li, C., Li, Y., Zhang, Z., Wang, J., Lu, Y., Yu, Q., Su, H., et al. Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(+) T cells. Immunity 44 (2016), 1337–1349.
60. 60 Koga, T., Hedrich, C.M., Mizui, M., Yoshida, N., Otomo, K., Lieberman, L.A., Rauen, T., Crispin, J.C., Tsokos, G.C., CaMK4-dependent activation of AKT/mTOR and CREM-alpha underlies autoimmunity-associated Th17 imbalance. J. Clin. Invest. 124 (2014), 2234–2245.
61. 61 Sinclair, L.V., Rolf, J., Emslie, E., Shi, Y.B., Taylor, P.M., Cantrell, D.A., Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14 (2013), 500–508.
62. 62 Finlay, D.K., Rosenzweig, E., Sinclair, L.V., Feijoo-Carnero, C., Hukelmann, J.L., Rolf, J., Panteleyev, A.A., Okkenhaug, K., Cantrell, D.A., PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209 (2012), 2441–2453.
63. 63 Ito, D., Nojima, S., Nishide, M., Okuno, T., Takamatsu, H., Kang, S., Kimura, T., Yoshida, Y., Morimoto, K., Maeda, Y., et al. mTOR complex signaling through the SEMA4A-plexin B2 axis is required for optimal activation and differentiation of CD8+ T cells. J. Immunol. 195 (2015), 934–943.
64. 64 Eil, R., Vodnala, S.K., Clever, D., Klebanoff, C.A., Sukumar, M., Pan, J.H., Palmer, D.C., Gros, A., Yamamoto, T.N., Patel, S.J., et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537 (2016), 539–543.
65. 65 Chang, J.T., Palanivel, V.R., Kinjyo, I., Schambach, F., Intlekofer, A.M., Banerjee, A., Longworth, S.A., Vinup, K.E., Mrass, P., Oliaro, J., et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315 (2007), 1687–1691.
66. 66•• Pollizzi, K.N., Sun, I.H., Patel, C.H., Lo, Y.C., Oh, M.H., Waickman, A.T., Tam, A.J., Blosser, R.L., Wen, J., Delgoffe, G.M., et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat. Immunol. 17 (2016), 704–711 Ref [66••] showed that asymmetric distribution of PI3K-mTOR signaling determines T cell fate. Low PI3K-mTOR-MYC predisposes cells to memory T cell differentiation, while high PI3K-mTOR-MYC skews cells to terminally differentiated effector cells.
67. 67•• Verbist, K.C., Guy, C.S., Milasta, S., Liedmann, S., Kaminski, M.M., Wang, R., Green, D.R., Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532 (2016), 389–393 Ref [67••] showed that asymmetric distribution of PI3K-mTOR signaling determines T cell fate. Low PI3K-mTOR-MYC predisposes cells to memory T cell differentiation, while high PI3K-mTOR-MYC skews cells to terminally differentiated effector cells.
68. 68 Lin, W.H., Adams, W.C., Nish, S.A., Chen, Y.H., Yen, B., Rothman, N.J., Kratchmarov, R., Okada, T., Klein, U., Reiner, S.L., Asymmetric PI3 K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep. 13 (2015), 2203–2218.