Toll-like Receptor-mediated Induction of Type I Interferon in Plasmacytoid Dendritic Cells Requires the Rapamycin-sensitive PI(3)K-mTOR-p70S6K Pathway

Overview

Journal Nat Immunol

Date 2008 Sep 2

PMID 18758466

Citations 218

Authors

Weiping Cao

Santhakumar Manicassamy

Hua Tang

Sudhir Pai Kasturi

Ali Pirani

Niren Murthy

Bali Pulendran

Affiliations

Soon will be listed here.

Abstract

Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs.

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References

Schreiber S . Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991; 251(4991):283-7. DOI: 10.1126/science.1702904. View

Shinohara M, Lu L, Bu J, Werneck M, Kobayashi K, Glimcher L . Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol. 2006; 7(5):498-506. PMC: 3725256. DOI: 10.1038/ni1327. View

Sigal N, Dumont F . Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992; 10:519-60. DOI: 10.1146/annurev.iy.10.040192.002511. View

Sarbassov D, Ali S, Sabatini D . Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005; 17(6):596-603. DOI: 10.1016/j.ceb.2005.09.009. View

Kozma S, Thomas G . Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays. 2002; 24(1):65-71. DOI: 10.1002/bies.10031. View

Gallucci S, Matzinger P . Danger signals: SOS to the immune system. Curr Opin Immunol. 2001; 13(1):114-9. DOI: 10.1016/s0952-7915(00)00191-6. View

Turnquist H, Raimondi G, Zahorchak A, Fischer R, Wang Z, Thomson A . Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol. 2007; 178(11):7018-31. DOI: 10.4049/jimmunol.178.11.7018. View

Latz E, Schoenemeyer A, Visintin A, Fitzgerald K, Monks B, Knetter C . TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004; 5(2):190-8. DOI: 10.1038/ni1028. View

Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K . Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000; 13(4):539-48. DOI: 10.1016/s1074-7613(00)00053-4. View

10.

P Monath T . Yellow fever vaccine. Expert Rev Vaccines. 2005; 4(4):553-74. DOI: 10.1586/14760584.4.4.553. View

11.

Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T . IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005; 434(7034):772-7. DOI: 10.1038/nature03464. View

12.

Kawai T, Akira S . Innate immune recognition of viral infection. Nat Immunol. 2006; 7(2):131-7. DOI: 10.1038/ni1303. View

13.

Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H . Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301(5633):640-3. DOI: 10.1126/science.1087262. View

14.

Colina R, Costa-Mattioli M, Dowling R, Jaramillo M, Tai L, Breitbach C . Translational control of the innate immune response through IRF-7. Nature. 2008; 452(7185):323-8. DOI: 10.1038/nature06730. View

15.

Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler L, Sonenberg N . eIF4E--from translation to transformation. Oncogene. 2004; 23(18):3172-9. DOI: 10.1038/sj.onc.1207549. View

16.

Marie I, Smith E, Prakash A, Levy D . Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain. Mol Cell Biol. 2000; 20(23):8803-14. PMC: 86519. DOI: 10.1128/MCB.20.23.8803-8814.2000. View

17.

Sehgal S . Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998; 31(5):335-40. DOI: 10.1016/s0009-9120(98)00045-9. View

18.

Singh M, Chakrapani A, OHagan D . Nanoparticles and microparticles as vaccine-delivery systems. Expert Rev Vaccines. 2007; 6(5):797-808. DOI: 10.1586/14760584.6.5.797. View

19.

Liu Y . IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005; 23:275-306. DOI: 10.1146/annurev.immunol.23.021704.115633. View

20.

Nave B, Ouwens M, Withers D, Alessi D, Shepherd P . Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999; 344 Pt 2:427-31. PMC: 1220660. View