Abstract
Surface-contact–mediated signaling induced by the measles virus (MV) fusion and hemagglutinin glycoproteins is necessary and sufficient to induce T-cell unresponsiveness in vitro and in vivo. To define the intracellular pathways involved, we analyzed interleukin (IL)-2R signaling in primary human T cells and in Kit-225 cells. Unlike IL-2–dependent activation of JAK/STAT pathways, activation of Akt kinase was impaired after MV contact both in vitro and in vivo. MV interference with Akt activation was important for immunosuppression, as expression of a catalytically active Akt prevented negative signaling by the MV glycoproteins. Thus, we show here that MV exploits a novel strategy to interfere with T-cell activation during immunosuppression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Borrow, P. & Oldstone, M.B.A. Measles virus—mononuclear cell interactions. in Measles virus. (eds. Billeter, M. & ter Meulen, V.) 85–100 (Springer, Berlin, 1995).
Griffin, D.E. Immune responses during measles virus infection. in Measles virus. (eds. Billeter, M. & ter Meulen, V.) 117–134 (Springer, Berlin, 1995).
Schneider-Schaulies, S. & ter Meulen, V. Pathogenic aspects of measles virus infection. Arch. Virol. Supp. 15, 139–158 (1999).
Schlender, J. et al. Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro. Proc. Natl. Acad. Sci. USA 93, 13194–13199 (1996).
Niewiesk, S. et al. Measles virus induced immunosuppression in the cotton rat (sigmodon hispidus) model depends on viral glycoproteins. J. Virol. 71, 7214–7219 (1997).
Engelking, O., Fedorov, L., Lilischkies, R., ter Meulen, V. & Schneider-Schaulies, S. Measles virus induced immunosuppression is associated with deregulation of cell cycle control proteins. J. Gen. Virol. 80, 1599–1608 (1999).
Weidmann, A. et al. The role of F protein proteolytic processing for the induction of measles virus induced immunosuppression. J. Virol. 74, 1985–1993 (2000).
Weidmann, A. et al. Measles virus induced immunosuppression in vitro is independent of complex glycosylation of the viral glycoproteins and of hemifusion. J. Virol. 74, 7548–7553 (2000).
Schnorr, J.J. et al. Cell cycle arrest rather than apoptosis is associated with measles virus induced immunosuppression in vitro. J. Gen. Virol. 78, 3217–3226 (1997).
Niewiesk, S. et al. Measles virus induced immunosuppression in cotton rats is associated with a cell cycle retardation in uninfected lymphocytes. J. Gen. Virol. 80, 2023–2029 (1999).
Smith, K.A. Interleukin-2: Inception, impact and implications. Science 240, 1169–1176 (1988).
Nelson, B.H., Lord, J.D. & Greenberg, P.D. Cytoplasmic domains of the IL-2Rβ and γ chain cytoplasmic domain are required for signaling. Nature 369, 333–337 (1994).
Migone, T.S. et al. Functional cooperation of the IL-2Rβ chain and Jak1 in PI3K recruitment and phosphorylation. Mol. Cell. Biol. 18, 6416–6422 (1998).
Lord, J.D., McIntosh, B.C., Greenberg, P.D. & Nelson, B.H. The IL-2R promotes proliferation, bcl-2 and bcl-x induction but not cell viability through the adaptor molecule Shc. J. Immunol. 161, 4627–4633 (1998).
Reif, K.B., Burgering, B.M.T. & Cantrell, D.A. Phosphatidylinositol-3 kinase links the interleukin-2 receptor to protein kinase B and p70S6 kinase. J. Biol. Chem. 272, 14426–14438 (1997).
Ahmed, N.N., Grimes, H.L., Bellacosa A., Chan, T.O. & Tsichlis, P.N. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc. Natl. Acad. Sci. USA 94, 3627–3632 (1997).
Chan, T.O., Rittenhouse, S.E. & Tsichlis, P.N. Akt/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Ann. Rev. Biochem. 68, 965–1014 (1999).
Kane, L.P., Shapiro, V., Stokoe, D. & Weiss, A. Induction of NFκB by the Akt/PKB kinase. Curr. Biol. 9, 601–604 (1999).
Brennan, P. et al. PI3K couples the interleukin-2 receptor to the cell cycle control machinery. Immunity 7, 679–689 (1997).
Brennan, P., Babbage, J.W., Thomas, R. & Cantrell, D. p70s6K integrates phosphoinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Mol. Cell. Biol. 19, 4729–4738 (1999).
Niewiesk, S., Götzelmann, M. & ter Meulen, V. Selective suppression of T lymphocyte responses in experimental measles infection. Proc. Natl. Acad. Sci. USA 97, 4251–4255 (2000).
Van Dooren, S. et al. Evidence for a post-columbian introduction of human T cell lymphotropic virus in Latin America. J. Gen. Virol. 79, 2695–2708 (1998)
Grassmann, R. et al. Role of human T cell leukemia virus type 1 X region proteins in immortalisation of primary human lymphocytes in culture. J. Virol. 66, 4570–4575 (1992).
Naniche, D., Reed, S.I. & Oldstone, M.B.A. Cell cycle arrest during measles virus infection: a G0 like block leads to suppression of retinoblastoma protein expression. J. Virol. 73, 1894–1901 (1999).
Rusterholz, C., Henrioud, P.C. & Nabholz, M. IL-2 regulates the accessibility of the IL-2 responsive element in the IL-2 receptor α gene to transcription factors. Mol. Cell. Biol. 19, 2681–2689 (1999).
Bell, A.F., Burns, J.B. & Fujinami, R.S. Measles virus infection of human T cells modulates cytokine generation and IL-2 receptor α chain expression. Virology 232, 241–247 (1997).
Moriggl, R. et al. Stat5 is required for IL-2 induced cell cycle progression of peripheral T cells. Immunity 10, 249–259 (1999).
Diehl, A., Cheng, M., Roussell, M.F. & Sherr, C.J. Glycogen synthase kinase 3β regulates cyclin D1 proteolysis and subcellular localisation. Genes Dev. 12, 3499–3511 (1998).
Muise-Helmerincks, R.C. et al. Cyclin D expression is controlled posttrancriptionally via a phosphatidylinositol 3-kinase/Akt dependent pathway. J. Biol. Chem. 273, 29864–29872 (1998).
Sun, H. et al. PTEN modulates cell cycle progression and cell survival by regulating phosphoinositol 3,4,5-triphosphate and Akt/PKB signaling pathway. Proc. Natl. Acad. Sci. USA 96, 6199–6204 (1999).
Delcommenne, M. et al. Phosphoinositide-3-OH kinase dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc. Natl. Acad. Sci. USA 95, 11211–11216 (1998).
Persad, S. et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of PKB/Akt and induces cell cycle arrest and apoptosis of PTEN mutant prostate cancer cells. Proc. Natl. Acad. Sci. USA 97, 3207–3212 (2000).
Ramaswamy, S. et al. Regulation of G1 progression by the PTEN tumor associated protein is linked to inhibition of the PI3K/Akt pathway. Proc. Natl. Acad. Sci. USA 96, 2110–2115 (1999).
Cantley, L.C. & Neel, B.G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3 kinase/Akt pathway. Proc. Natl. Acad. Sci. 96, 4240–4245 (1999).
Jones, R.G. et al. Protein kinase B regulates T lymphocytes survival, nuclear factor κB activation and Bcl-XL levels in vivo. J. Exp. Med. 191, 1721–1733 (2000).
Hinton, H. & Welham, M.J. Cytokine-induced protein kinase B activation and Bad phosphorylation do not correlate with cell survival of hematopoetic cells. J. Immunol. 162, 7002–7009 (1999).
Meili, R., Cron, P., Hemmings, P. & Ballmer-Hofer, K. Protein kinase B/Akt is activated by polyomavirus middle T antigen via a PI3K dependent mechanism. Oncogene 19, 903–907 (1998).
Borgatti, P. et al. Extracellular HIV-1 Tat protein activates PI3K and Akt kinase in CD4+ T lymphoblastoid Jurkat cells. Eur. J. Immunol. 27, 2805–2811 (1997).
Dörig, R.E., Marcil, A., Chopra, A. & Richardson, C. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295–305 (1993)
Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993)
Spielhofer, P. et al. Chimeric measles viruses expressing a foreign envelope gene. J. Virol. 72, 2150–2159 (1998).
Andjelkovic, M. et al. Role of translocation in the activation of protein kinase B. J. Biol. Chem. 272, 31515–31524 (1997).
Zhumabekov, T., Corbella, P., Tolaini, M. & Kioussis, D. Improved version of a human CD2 minigene based vector for T-cell-specific expression in transgenic mice. J. Immunol. Meth. 185, 133–140 (1995).
Bright, J.J., Kerr, L.D. & Sriram, S. TGF-β inhibits IL-2 induced tyrosine phosphorylation and activation of JAK1 and STAT5 in T lymphocytes. J. Immunol. 158,175–183 (1997).
Avots, A. et al. GABP factors bind to a distal interleukin 2 (IL-2) enhancer and contribute to c-Raf-mediated increase in IL-2 induction. Mol. Cell. Biol. 17, 4381–4389 (1997).
Acknowledgements
We thank J. Schneider-Schaulies, A. Weidmann, I. Klagge and E. Serfling for helpful discussions; R. Grassmann for providing C91PL, JuanaW and HTLV-I Tax-transformed TAXI-1 cells; D. Cantrell for providing Kit-225 cells; and C. Rüth for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft and the Bundesministerium Bildung and Forschung.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Avota, E., Avots, A., Niewiesk, S. et al. Disruption of Akt kinase activation is important for immunosuppression induced by measles virus. Nat Med 7, 725–731 (2001). https://doi.org/10.1038/89106
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/89106
This article is cited by
-
The consequences of viral infection on host DNA damage response: a focus on SARS-CoVs
Journal of Genetic Engineering and Biotechnology (2022)
-
Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response
Cellular & Molecular Immunology (2016)
-
Inhibition of the PI3K/Akt pathway by Ly294002 does not prevent establishment of persistent Junín virus infection in Vero cells
Archives of Virology (2015)
-
Measles virus-induced immunosuppression: from effectors to mechanisms
Medical Microbiology and Immunology (2010)