Advertisement

Virologica Sinica

, Volume 30, Issue 3, pp 174–189 | Cite as

mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines

  • Li He
  • Aiping Zang
  • Min Du
  • Dapeng Ma
  • Chuanping Yuan
  • Chun Zhou
  • Jing Mu
  • Huanjing Shi
  • Dapeng Li
  • Xulin Huang
  • Qiang Deng
  • Jianhua Xiao
  • Huimin Yan
  • Lijian Hui
  • Ke Lan
  • Sidong Xiong
  • Xiaoxia Li
  • Zhong Huang
  • Hui XiaoEmail author
Research Article

Abstract

Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte (CTL) responses, Toll-like receptor (TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3K, ERK, and mTOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, mTOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of mTOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which mTOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.

Keywords

Toll-like receptor (TLR) mTOR vaccine hepatitis B virus (HBV) hepatitis C virus (HCV) adjuvant c-fos 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno IM, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B. 2012. The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol, 13: 1045–1054.PubMedCentralPubMedCrossRefGoogle Scholar
  2. Almawi WY, Melemedjian OK. 2000. Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. Nephrol Dial Transplant, 15: 1916–1918.PubMedCrossRefGoogle Scholar
  3. Amiel E, Everts B, Freitas TC, King IL, Curtis JD, Pearce EL, Pearce EJ. 2012. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J Immunol, 189: 2151–2158.CrossRefGoogle Scholar
  4. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  5. Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, Parham P, Walker CM. 1999. Analysis of a successful immune response against hepatitis C virus. Immunity, 10: 439–449.PubMedCrossRefGoogle Scholar
  6. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, Ray SC. 2005. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology, 42: 104–112.PubMedCentralPubMedCrossRefGoogle Scholar
  7. Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A, Maliszewski C, Akira S, Pulendran B. 2004. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol, 172: 4733–4743.PubMedCrossRefGoogle Scholar
  8. Haidinger M, Poglitsch M, Geyeregger R, Kasturi S, Zeyda M, Zlabinger GJ, Pulendran B, Horl WH, Saemann MD, Weichhart T. 2010. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol, 185: 3919–3931.PubMedCrossRefGoogle Scholar
  9. Huang J, Manning BD. 2008. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J, 412: 179–190.PubMedCentralPubMedCrossRefGoogle Scholar
  10. Iwasaki A, Medzhitov R. 2010. Regulation of adaptive immunity by the innate immune system. Science, 327: 291–295.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Jagannath C, Bakhru P. 2012. Rapamycin-induced enhancement of vaccine efficacy in mice. Methods Mol Biol, 821: 295–303.PubMedCentralPubMedCrossRefGoogle Scholar
  12. Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, Yang HT, Grant S, Ricciardi-Castagnoli P, Tsichlis PN, Ley SC, O’Garra A. 2009. TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. J Exp Med, 206: 1863–1871.PubMedCentralPubMedCrossRefGoogle Scholar
  13. Kundi M. 2007. New hepatitis B vaccine formulated with an improved adjuvant system. Expert Rev Vaccines, 6: 133–140.PubMedCrossRefGoogle Scholar
  14. Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell, 149: 274–293.PubMedCentralPubMedCrossRefGoogle Scholar
  15. Li Q, Rao RR, Araki K, Pollizzi K, Odunsi K, Powell JD, Shrikant PA. 2011. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity, 34: 541–553.PubMedCentralPubMedCrossRefGoogle Scholar
  16. Lyakh L, Trinchieri G, Provezza L, Carra G, Gerosa F. 2008. Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol Rev, 226: 112–131.PubMedCentralPubMedCrossRefGoogle Scholar
  17. Min L, Ji Y, Bakiri L, Qiu Z, Cen J, Chen X, Chen L, Scheuch H, Zheng H, Qin L, Zatloukal K, Hui L, Wagner EF. 2012. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol, 14: 1203–1211.PubMedCrossRefGoogle Scholar
  18. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. 2001. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol, 19: 683–765.PubMedCrossRefGoogle Scholar
  19. Naarding MA, Falkowska E, Xiao H, Dragic T. 2011. Hepatitis C virus soluble E2 in combination with QuilA and CpG ODN induces neutralizing antibodies in mice. Vaccine, 29: 2910–2917.PubMedCrossRefGoogle Scholar
  20. Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. 2005. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol, 6: 769–776.PubMedCentralPubMedCrossRefGoogle Scholar
  21. Ohtani M, Nagai S, Kondo S, Mizuno S, Nakamura K, Tanabe M, Takeuchi T, Matsuda S, Koyasu S. 2008. Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood, 112: 635–643.PubMedCentralPubMedCrossRefGoogle Scholar
  22. Pan H, O’Brien TF, Zhang P, Zhong XP. 2012. The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol, 188: 3658–3666.PubMedCentralPubMedCrossRefGoogle Scholar
  23. Pichichero ME. 2008. Improving vaccine delivery using novel adjuvant systems. Hum Vaccin, 4: 262–270.PubMedCrossRefGoogle Scholar
  24. Qiu Q, Wang RY, Jiao X, Jin B, Sugauchi F, Grandinetti T, Alter HJ, Shih JW. 2008. Induction of multispecific Th-1 type immune response against HCV in mice by protein immunization using CpG and Montanide ISA 720 as adjuvants. Vaccine, 26: 5527–5534.PubMedCrossRefGoogle Scholar
  25. Saraiva M, O’Garra A. 2010. The regulation of IL-10 production by immune cells. Nat Rev Immunol, 10: 170–181.PubMedCrossRefGoogle Scholar
  26. Schmitz F, Heit A, Dreher S, Eisenacher K, Mages J, Haas T, Krug A, Janssen KP, Kirschning CJ, Wagner H. 2008. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol, 38: 2981–2992.PubMedCrossRefGoogle Scholar
  27. Swadling L, Klenerman P, Barnes E. 2013. Ever closer to a prophylactic vaccine for HCV. Expert Opin Biol Ther, 13: 1109–1124.PubMedCentralPubMedCrossRefGoogle Scholar
  28. Thoelen S, Van Damme P, Mathei C, Leroux-Roels G, Desombere I, Safary A, Vandepapeliere P, Slaoui M, Meheus A. 1998. Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system. Vaccine, 16: 708–714.PubMedCrossRefGoogle Scholar
  29. Tong NK, Beran J, Kee SA, Miguel JL, Sanchez C, Bayas JM, Vilella A, de Juanes JR, Arrazola P, Calbo-Torrecillas F, de Novales EL, Hamtiaux V, Lievens M, Stoffel M. 2005. Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int, 68: 2298–2303.PubMedCrossRefGoogle Scholar
  30. Torresi J, Johnson D, Wedemeyer H. 2011. Progress in the development of preventive and therapeutic vaccines for hepatitis C virus. J Hepatol, 54: 1273–1285.PubMedCrossRefGoogle Scholar
  31. Trinchieri G. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol, 3: 133–146.PubMedCrossRefGoogle Scholar
  32. Trinchieri G, Sher A. 2007. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol, 7: 179–190.PubMedCrossRefGoogle Scholar
  33. Wang H, Brown J, Gu Z, Garcia CA, Liang R, Alard P, Beurel E, Jope RS, Greenway T, Martin M. 2011. Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-beta-signaling pathways regulates the innate inflammatory response. J Immunol, 186: 5217–5226.PubMedCentralPubMedCrossRefGoogle Scholar
  34. Warger T, Osterloh P, Rechtsteiner G, Fassbender M, Heib V, Schmid B, Schmitt E, Schild H, Radsak MP. 2006. Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood, 108: 544–550.PubMedCrossRefGoogle Scholar
  35. Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM, Kolbe T, Stulnig TM, Horl WH, Hengstschlager M, Muller M, Saemann MD. 2008. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity, 29: 565–577.PubMedCrossRefGoogle Scholar
  36. Weintz G, Olsen JV, Fruhauf K, Niedzielska M, Amit I, Jantsch J, Mages J, Frech C, Dolken L, Mann M, Lang R. 2010. The phosphoproteome of toll-like receptor-activated macrophages. Mol Syst Biol, 6: 371.PubMedCentralPubMedCrossRefGoogle Scholar
  37. Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J, Zhang H, Wang R, Yang Z, Zhang L, Zhao Y. 2014. TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun, 5: 4696.PubMedCrossRefGoogle Scholar
  38. Zhu Q, Egelston C, Vivekanandhan A, Uematsu S, Akira S, Klinman DM, Belyakov IM, Berzofsky JA. 2008. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc Natl Acad Sci U S A, 105: 16260–16265.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Li He
    • 1
    • 2
  • Aiping Zang
    • 2
  • Min Du
    • 2
  • Dapeng Ma
    • 2
    • 3
  • Chuanping Yuan
    • 2
  • Chun Zhou
    • 2
  • Jing Mu
    • 2
  • Huanjing Shi
    • 2
  • Dapeng Li
    • 4
  • Xulin Huang
    • 4
  • Qiang Deng
    • 5
  • Jianhua Xiao
    • 3
  • Huimin Yan
    • 6
  • Lijian Hui
    • 7
  • Ke Lan
    • 5
  • Sidong Xiong
    • 1
  • Xiaoxia Li
    • 8
  • Zhong Huang
    • 4
    • 9
  • Hui Xiao
    • 2
    • 9
    Email author
  1. 1.Institute of Biology and Medical SciencesSoochow UniversitySoochowChina
  2. 2.Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
  3. 3.Institute of Pathogenic BiologyUniversity of South ChinaHengyangChina
  4. 4.Unit of Vaccinology and Anti-viral Strategies, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
  5. 5.Unit of Tumor Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
  6. 6.Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of VirologyChinese Academy of SciencesWuhanChina
  7. 7.State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  8. 8.Department of Immunology, Lerner Research InstituteCleveland Clinic FoundationClevelandUSA
  9. 9.Vaccine Center, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina

Personalised recommendations