Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Sep 1;180(3):841–850. doi: 10.1084/jem.180.3.841

Upregulation of class I major histocompatibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo

PMCID: PMC2191654  PMID: 8064236

Abstract

Major histocompatibility complex (MHC) deficiency is typical of almost all resident cells in normal neural tissue. However, CD8+ T cells, which recognize antigenic peptides in the context of class I MHC molecules, are known to mediate clearance of herpes simplex virus (HSV) from spinal ganglia of experimentally infected mice, leading to the hypothesis that class I expression in the peripheral nervous system must be upregulated in response to HSV infection. In addressing this hypothesis it is shown, in BALB/c (H-2d) mice, that normally deficient class I transcripts transiently accumulate in peripheral nerve Schwann cells, ganglionic satellite cells, and primary sensory neurons, indicating that in each of these cell types class I expression is regulated at the transcriptional level in vivo. Furthermore, for 3-4 wk after infection, H-2Kd/Dd antigens are expressed by satellite and Schwann cells but not neurons, suggesting additional posttranscriptional regulation of class I synthesis in neurons. Alternatively, the class I RNAs induced in neurons may not be derived from classical class I genes. Factors regulating H-2 class I expression emanate from within infected ganglia, probably from infected neurons themselves. However, induction of class I molecules was not maintained during latency, when viral gene expression in neurons is restricted to a single region within the virus repeats. These data have implications for the long-term survival of cells in HSV-infected neural tissue.

Full Text

The Full Text of this article is available as a PDF (4.9 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arthur J., Efstathiou S., Simmons A. Intranuclear foci containing low abundance herpes simplex virus latency-associated transcripts visualized by non-isotopic in situ hybridization. J Gen Virol. 1993 Jul;74(Pt 7):1363–1370. doi: 10.1099/0022-1317-74-7-1363. [DOI] [PubMed] [Google Scholar]
  2. Breakefield X. O., DeLuca N. A. Herpes simplex virus for gene delivery to neurons. New Biol. 1991 Mar;3(3):203–218. [PubMed] [Google Scholar]
  3. Cabrera C. V., Wohlenberg C., Openshaw H., Rey-Mendez M., Puga A., Notkins A. L. Herpes simplex virus DNA sequences in the CNS of latently infected mice. Nature. 1980 Nov 20;288(5788):288–290. doi: 10.1038/288288a0. [DOI] [PubMed] [Google Scholar]
  4. Cook M. L., Bastone V. B., Stevens J. G. Evidence that neurons harbor latent herpes simplex virus. Infect Immun. 1974 May;9(5):946–951. doi: 10.1128/iai.9.5.946-951.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cook M. L., Stevens J. G. Pathogenesis of herpetic neuritis and ganglionitis in mice: evidence for intra-axonal transport of infection. Infect Immun. 1973 Feb;7(2):272–288. doi: 10.1128/iai.7.2.272-288.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coupar B. E., Andrew M. E., Boyle D. B., Blanden R. V. Immune responses to H-2Kd antigen expressed by recombinant vaccinia virus. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7879–7882. doi: 10.1073/pnas.83.20.7879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dillard S. H., Cheatham W. J., Moses H. L. Electron microscopy of zosteriform herpes simplex infection in the mouse. Lab Invest. 1972 Apr;26(4):391–402. [PubMed] [Google Scholar]
  8. Doerig C., Pizer L. I., Wilcox C. L. An antigen encoded by the latency-associated transcript in neuronal cell cultures latently infected with herpes simplex virus type 1. J Virol. 1991 May;65(5):2724–2727. doi: 10.1128/jvi.65.5.2724-2727.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Efstathiou S., Kemp S., Darby G., Minson A. C. The role of herpes simplex virus type 1 thymidine kinase in pathogenesis. J Gen Virol. 1989 Apr;70(Pt 4):869–879. doi: 10.1099/0022-1317-70-4-869. [DOI] [PubMed] [Google Scholar]
  10. Israel A., Kimura A., Fournier A., Fellous M., Kourilsky P. Interferon response sequence potentiates activity of an enhancer in the promoter region of a mouse H-2 gene. Nature. 1986 Aug 21;322(6081):743–746. doi: 10.1038/322743a0. [DOI] [PubMed] [Google Scholar]
  11. Jameson S. C., Tope W. D., Tredgett E. M., Windle J. M., Diamond A. G., Howard J. C. Cloning and expression of class I major histocompatibility complex genes of the rat. J Exp Med. 1992 Jun 1;175(6):1749–1757. doi: 10.1084/jem.175.6.1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Joly E., Mucke L., Oldstone M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 1991 Sep 13;253(5025):1283–1285. doi: 10.1126/science.1891717. [DOI] [PubMed] [Google Scholar]
  13. Joly E., Oldstone M. B. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron. 1992 Jun;8(6):1185–1190. doi: 10.1016/0896-6273(92)90138-4. [DOI] [PubMed] [Google Scholar]
  14. Kimura A., Israël A., Le Bail O., Kourilsky P. Detailed analysis of the mouse H-2Kb promoter: enhancer-like sequences and their role in the regulation of class I gene expression. Cell. 1986 Jan 31;44(2):261–272. doi: 10.1016/0092-8674(86)90760-9. [DOI] [PubMed] [Google Scholar]
  15. Kosz-Vnenchak M., Jacobson J., Coen D. M., Knipe D. M. Evidence for a novel regulatory pathway for herpes simplex virus gene expression in trigeminal ganglion neurons. J Virol. 1993 Sep;67(9):5383–5393. doi: 10.1128/jvi.67.9.5383-5393.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kurlander R. J., Shawar S. M., Brown M. L., Rich R. R. Specialized role for a murine class I-b MHC molecule in prokaryotic host defenses. Science. 1992 Jul 31;257(5070):678–679. doi: 10.1126/science.1496381. [DOI] [PubMed] [Google Scholar]
  17. Leung K. N., Nash A. A., Sia D. Y., Wildy P. Clonal analysis of T-cell responses to herpes simplex virus: isolation, characterization and antiviral properties of an antigen-specific helper T-cell clone. Immunology. 1984 Dec;53(4):623–633. [PMC free article] [PubMed] [Google Scholar]
  18. Levine B., Hardwick J. M., Trapp B. D., Crawford T. O., Bollinger R. C., Griffin D. E. Antibody-mediated clearance of alphavirus infection from neurons. Science. 1991 Nov 8;254(5033):856–860. doi: 10.1126/science.1658936. [DOI] [PubMed] [Google Scholar]
  19. Ljungdahl A., Olsson T., Van der Meide P. H., Holmdahl R., Klareskog L., Höjeberg B. Interferon-gamma-like immunoreactivity in certain neurons of the central and peripheral nervous system. J Neurosci Res. 1989 Nov;24(3):451–456. doi: 10.1002/jnr.490240316. [DOI] [PubMed] [Google Scholar]
  20. Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
  21. Massa P. T., Ozato K., McFarlin D. E. Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes, and neurons. Glia. 1993 Jul;8(3):201–207. doi: 10.1002/glia.440080307. [DOI] [PubMed] [Google Scholar]
  22. Minty A. J., Caravatti M., Robert B., Cohen A., Daubas P., Weydert A., Gros F., Buckingham M. E. Mouse actin messenger RNAs. Construction and characterization of a recombinant plasmid molecule containing a complementary DNA transcript of mouse alpha-actin mRNA. J Biol Chem. 1981 Jan 25;256(2):1008–1014. [PubMed] [Google Scholar]
  23. Nash A. A., Jayasuriya A., Phelan J., Cobbold S. P., Waldmann H., Prospero T. Different roles for L3T4+ and Lyt 2+ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system. J Gen Virol. 1987 Mar;68(Pt 3):825–833. doi: 10.1099/0022-1317-68-3-825. [DOI] [PubMed] [Google Scholar]
  24. Oldstone M. B. Molecular anatomy of viral persistence. J Virol. 1991 Dec;65(12):6381–6386. doi: 10.1128/jvi.65.12.6381-6386.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Parnes J. R., Seidman J. G. Structure of wild-type and mutant mouse beta 2-microglobulin genes. Cell. 1982 Jun;29(2):661–669. doi: 10.1016/0092-8674(82)90182-9. [DOI] [PubMed] [Google Scholar]
  26. Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
  27. Sedgwick J. D., Mössner R., Schwender S., ter Meulen V. Major histocompatibility complex-expressing nonhematopoietic astroglial cells prime only CD8+ T lymphocytes: astroglial cells as perpetuators but not initiators of CD4+ T cell responses in the central nervous system. J Exp Med. 1991 May 1;173(5):1235–1246. doi: 10.1084/jem.173.5.1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Simmons A. H-2-linked genes influence the severity of herpes simplex virus infection of the peripheral nervous system. J Exp Med. 1989 Apr 1;169(4):1503–1507. doi: 10.1084/jem.169.4.1503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Simmons A., La Vista A. B. Neural infection in mice after cutaneous inoculation with HSV-1 is under complex host genetic control. Virus Res. 1989 Jul;13(3):263–270. doi: 10.1016/0168-1702(89)90020-8. [DOI] [PubMed] [Google Scholar]
  30. Simmons A., Nash A. A. Effect of B cell suppression on primary infection and reinfection of mice with herpes simplex virus. J Infect Dis. 1987 Apr;155(4):649–654. doi: 10.1093/infdis/155.4.649. [DOI] [PubMed] [Google Scholar]
  31. Simmons A., Nash A. A. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J Virol. 1984 Dec;52(3):816–821. doi: 10.1128/jvi.52.3.816-821.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Simmons A., Tscharke D. C. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J Exp Med. 1992 May 1;175(5):1337–1344. doi: 10.1084/jem.175.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Speck P. G., Simmons A. Synchronous appearance of antigen-positive and latently infected neurons in spinal ganglia of mice infected with a virulent strain of herpes simplex virus. J Gen Virol. 1992 May;73(Pt 5):1281–1285. doi: 10.1099/0022-1317-73-5-1281. [DOI] [PubMed] [Google Scholar]
  34. Stevens J. G. Human herpesviruses: a consideration of the latent state. Microbiol Rev. 1989 Sep;53(3):318–332. doi: 10.1128/mr.53.3.318-332.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Turnley A. M., Morahan G., Okano H., Bernard O., Mikoshiba K., Allison J., Bartlett P. F., Miller J. F. Dysmyelination in transgenic mice resulting from expression of class I histocompatibility molecules in oligodendrocytes. Nature. 1991 Oct 10;353(6344):566–569. doi: 10.1038/353566a0. [DOI] [PubMed] [Google Scholar]
  36. Ugolini G., Kuypers H. G., Simmons A. Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones. Brain Res. 1987 Oct 6;422(2):242–256. doi: 10.1016/0006-8993(87)90931-0. [DOI] [PubMed] [Google Scholar]
  37. Wong G. H., Bartlett P. F., Clark-Lewis I., McKimm-Breschkin J. L., Schrader J. W. Interferon-gamma induces the expression of H-2 and Ia antigens on brain cells. J Neuroimmunol. 1985 Feb-Mar;7(5-6):255–278. doi: 10.1016/s0165-5728(84)80026-0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES