Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2008;14(3):261–266. doi: 10.1080/13550280802105002

NKG2D contributes to efficient clearance of picornavirus from the acutely infected murine brain

Chandra Deb 1, Charles L Howe 1,2,3,4,5,✉
PMCID: PMC3181148  NIHMSID: NIHMS324983  PMID: 18569460

Abstract

Activated murine cytotoxic T cells express the NKG2D natural cytotoxicity receptor. This receptor recognizes major histocompatibility complex (MHC) class I-like molecules expressed on the surface of infected cells and serves to augment T cell-mediated cytotoxicity. The role of NKG2D-mediated augmentation in the clearance of central nervous system viral infections has not been explored. Using the Theiler’s murine encephalomyelitis virus model, the authors found that NKG2D-positive CD8+ cytotoxic T cells enter the brain, that NKG2D ligands are expressed in the brain during acute infection, and that interruption of NKG2D ligand recognition via treatment with a function-blocking antibody attenuates the efficacy of viral clearance from the central nervous system.

Keywords: cytotoxic T cell, enterovirus, H60, Mult1, neurovirulence, Rae1, TMEV

Footnotes

This work was supported by a grant from the National Multiple Sclerosis Society (RG3636), by an early career development award from the Mayo Clinic (CLH), and by Donald and Frances Herdrich.

References

  1. Baba T, Ishizu A, Iwasaki S, Suzuki A, Tomaru U, Ikeda H, Yoshiki T, Kasahara M. CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood. 2006;107:2004–2012. doi: 10.1182/blood-2005-06-2345. [DOI] [PubMed] [Google Scholar]
  2. Buenz EJ, Howe CL. Picornaviruses and cell death. Trends Microbiol. 2006;14:28–36. doi: 10.1016/j.tim.2005.11.003. [DOI] [PubMed] [Google Scholar]
  3. Buenz EJ, Rodriguez M, Howe CL. Disrupted spatial memory is a consequence of picornavirus infection. Neurobiol Dis. 2006;24:266–273. doi: 10.1016/j.nbd.2006.07.003. [DOI] [PubMed] [Google Scholar]
  4. Dandekar AA, O’Malley K, Perlman S. Important roles for gamma interferon and NKG2D in gammadelta T-cell-induced demyelination in T-cell receptor beta-deficient mice infected with a coronavirus. J Virol. 2005;79:9388–9396. doi: 10.1128/JVI.79.15.9388-9396.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eagle RA, Trowsdale J. Promiscuity and the single receptor: NKG2D. Nat Rev Immunol. 2007;7:737–744. doi: 10.1038/nri2144. [DOI] [PubMed] [Google Scholar]
  6. Hasan M, Krmpotic A, Ruzsics Z, Bubic I, Lenac T, Halenius A, Loewendorf A, Messerle M, Hengel H, Jonjic S, Koszinowski UH. Selective down-regulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. J Virol. 2005;79:2920–2930. doi: 10.1128/JVI.79.5.2920-2930.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Howe CL, Bieber AJ, Warrington AE, Pease LR, Rodriguez M. Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis. 2004;15:120–131. doi: 10.1016/j.nbd.2003.09.002. [DOI] [PubMed] [Google Scholar]
  8. Howe CL, Ure D, Adelson JD, LaFrance-Corey R, Johnson A, Rodriguez M. CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination. J Neuroimmunol. 2007;188:13–21. doi: 10.1016/j.jneuroim.2007.04.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jin YH, Mohindru M, Kang MH, Fuller AC, Kang B, Gallo D, Kim BS. Differential virus replication, cytokine production, and antigen-presenting function by microglia from susceptible and resistant mice infected with Theiler’s virus. J Virol. 2007;81:11690–11702. doi: 10.1128/JVI.01034-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kim J, Chang CK, Hayden T, Liu FC, Benjamin J, Hamerman JA, Lanier LL, Kang SM. The activating immunoreceptor NKG2D and its ligands are involved in allograft transplant rejection. J Immunol. 2007;179:6416–6420. doi: 10.4049/jimmunol.179.10.6416. [DOI] [PubMed] [Google Scholar]
  11. Lodoen M, Ogasawara K, Hamerman JA, Arase H, Houchins JP, Mocarski ES, Lanier LL. NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J Exp Med. 2003;197:1245–1253. doi: 10.1084/jem.20021973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lodoen MB, Abenes G, Umamoto S, Houchins JP, Liu F, Lanier LL. The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. J Exp Med. 2004;200:1075–1081. doi: 10.1084/jem.20040583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Markiewicz MA, Carayannopoulos LN, Naidenko OV, Matsui K, Burack WR, Wise EL, Fremont DH, Allen PM, Yokoyama WM, Colonna M, Shaw AS. Costimulation through NKG2D enhances murine CD8+ CTL function: similarities and differences between NKG2D and CD28 costimulation. J Immunol. 2005;175:2825–2833. doi: 10.4049/jimmunol.175.5.2825. [DOI] [PubMed] [Google Scholar]
  14. Mendez-Fernandez YV, Hansen MJ, Rodriguez M, Pease LR. Anatomical and cellular requirements for the activation and migration of virus-specific CD8+ T cells to the brain during Theiler’s virus infection. J Virol. 2005;79:3063–3070. doi: 10.1128/JVI.79.5.3063-3070.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mendez-Fernandez YV, Johnson AJ, Rodriguez M, Pease LR. Clearance of Theiler’s virus infection depends on the ability to generate a CD8+ T cell response against a single immunodominant viral peptide. Eur J Immunol. 2003;33:2501–2510. doi: 10.1002/eji.200324007. [DOI] [PubMed] [Google Scholar]
  16. Myoung J, Hou W, Kang B, Lyman MA, Kang JA, Kim BS. The immunodominant CD8+ T cell epitope region of Theiler’s virus in resistant C57BL/6 mice is critical for anti-viral immune responses, viral persistence, and binding to the host cells. Virology. 2007;360:159–171. doi: 10.1016/j.virol.2006.09.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ogasawara K, Hamerman JA, Hsin H, Chikuma S, Bour-Jordan H, Chen T, Pertel T, Carnaud C, Bluestone JA, Lanier LL. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity. 2003;18:41–51. doi: 10.1016/S1074-7613(02)00505-8. [DOI] [PubMed] [Google Scholar]
  18. Pavelko KD, van Engelen BG, Rodriguez M. Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci. 1998;18:2498–2505. doi: 10.1523/JNEUROSCI.18-07-02498.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3:781–790. doi: 10.1038/nri1199. [DOI] [PubMed] [Google Scholar]
  20. Rotbart HA. Clinical significance, diagnosis, and treatment of picornavirus infections. In: Semler BL, Wimmer E, editors. Molecular biology of Picornaviruses. Washington, DC: ASM Press; 2002. pp. 357–365. [Google Scholar]
  21. Rubio N, Sanz-Rodriguez F, Lipton HL. Theiler’s virus induces the MIP-2 chemokine (CXCL2) in astrocytes from genetically susceptible but not from resistant mouse strains. Cell Immunol. 2006;239:31–40. doi: 10.1016/j.cellimm.2006.03.003. [DOI] [PubMed] [Google Scholar]
  22. Saez-Borderias A, Guma M, Angulo A, Bellosillo B, Pende D, Lopez-Botet M. Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus. Eur J Immunol. 2006;36:3198–3206. doi: 10.1002/eji.200636682. [DOI] [PubMed] [Google Scholar]
  23. Takada A, Yoshida S, Kajikawa M, Miyatake Y, Tomaru U, Sakai M, Chiba H, Maenaka K, Kohda D, Fugo K, Kasahara M. Two Novel NKG2D ligands of the mouse H60 family with differential expression patterns and binding affinities to NKG2D. J Immunol. 2008;180:1678–1685. doi: 10.4049/jimmunol.180.3.1678. [DOI] [PubMed] [Google Scholar]
  24. Tsunoda I, Libbey JE, Kobayashi-Warren M, Fujinami RS. IFN-gamma production and astrocyte recognition by autoreactive T cells induced by Theiler’s virus infection: role of viral strains and capsid proteins. J Neuroimmunol. 2006;172:85–93. doi: 10.1016/j.jneuroim.2005.11.004. [DOI] [PubMed] [Google Scholar]
  25. Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A. 2007;104:18187–18192. doi: 10.1073/pnas.0708968104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wada Y, Fujinami RS. Viral infection and dissemination through the olfactory pathway and the limbic system by Theiler’s virus. Am J Pathol. 1993;143:221–229. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Neurovirology are provided here courtesy of Nature Publishing Group

RESOURCES