CNS Neurons: The Basis and Benefits of Low Class I Major Histocompatibility Complex Expression

  • Glenn F. Rall
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 232)


The host immune response is generally thought to consist of cells with “professional” immunologic functions, such as B and T cells, macrophages, and natural killer (NK) cells. However, differentiated cells which do not normally participate in immune surveillance may be recruited to serve an integral function in the immune-mediated elimination of foreign intracellular pathogens such as viruses. As discussed elsewhere in this volume, most cells have the ability to present immunogenic, “non-self” peptides (called epitopes) in association with “self&” class I major histocompatibility complex (MHC) molecules. This cell surface complex is engaged by the T cell receptor (TCR) of cytotoxic T lymphocytes (CTL). Appropriate MHC-epitope-TCR interaction leads to the CTL-mediated lysis of the epitope-expressing target cell via the perforation of the plasma membrane, introduction of CTL-derived proteolytic enzymes (granzymes) into the target cell cytosol, and eventual cell death, presumably via apoptosis.


Major Histocompatibility Complex Major Histocompatibility Complex Class Central Nervous System Neuron Measle Virus Infection Major Histocompatibility Complex Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bartlett PF, Kerr RSC, Bailey KA (1989) Expression of MHC antigens in the central nervous system. Transplant Proc 21:3163–3165PubMedGoogle Scholar
  2. Bergelson LD (1995) Serum gangliosides as endogenous immunomodulators. Immunol Today 16:483486CrossRefGoogle Scholar
  3. Bernards R, Dessain SK, Weinberg RA (1986) N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell 47:667–674PubMedCrossRefGoogle Scholar
  4. Bianchi L, Gudat F (1980) In: Bianchi L, Gerok W, Sickinger K (eds) Virus and the liver. MTP, Lancaster, pp 197–204Google Scholar
  5. Bilzer T, Stitz L (1994) Immune-mediated brain atrophy: CD8+ T cells contribute to tissue destruction during Boma disease. J Immunol 153:818–823PubMedGoogle Scholar
  6. Brightman MW, Zis K, Anders J (1983) Morphology of cerebral endothelium and astrocytes as determinants of the neuronal microenvironment. Acta Neuropathol Supl 8:21–33CrossRefGoogle Scholar
  7. Burke PA, Ozato K (1989) Regulation of major histocompatibility complex class I genes. Year Immunol 4:23–40PubMedGoogle Scholar
  8. Carosella ED, Dausset J, Kirszenbaum M (1996) HLA-G revisited. Immunol Today 17:407–409PubMedCrossRefGoogle Scholar
  9. Chumbley G, King A, Robertson K, Holmes N, Loke YW (1994) Resistance of HLA-G and HLA-A2 transfectants to lysis by decidual NK cells. Cell Immunol 155:312–322PubMedCrossRefGoogle Scholar
  10. Cserr HF, Knopf PM (1992) Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol Today 13:507–512PubMedCrossRefGoogle Scholar
  11. Cserr H, Harling-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–276PubMedCrossRefGoogle Scholar
  12. David-Watine B, Israel A, Kourilsky P (1990) The regulation and expression of MHC class I genes. Immunol Today 11:286–292PubMedCrossRefGoogle Scholar
  13. de la Torre JC, Rail G, Oldstone C, Sanna PP, Borrow P, Oldstone MBA (1993) Replication of lymphocytic choriomeningitis virus is restricted in terminally differentiated neurons. J Virol 67:7350–7359PubMedGoogle Scholar
  14. Deschamps J, Mitchell RL, Meijlink F, Kruijer W, Schubert D, Verma IM (1985) Proto-oncogene fos is expressed during development, differentiation, and growth. Cold Spring Harbor Symp Quant Biol 50:733–745PubMedGoogle Scholar
  15. Drew PD, Lonergan M, Goldstein ME, Lampson LA, Ozato K, McFarlin DE (1993) Regulation of MHC class I and (32 microglobulin gene expression in human neuronal cells. Factor binding to conserved cis-acting regulatory sequences correlates with expression of the genes. J Immunol 150:3300–3310PubMedGoogle Scholar
  16. Duguid J, Trzepacz C (1993) Major histocompatibility complex genes have an increased brain expression after scrapie infection. Proc Natl Acad Sci USA 90:114–117PubMedCrossRefGoogle Scholar
  17. Dyatlovitskaya EV, Bergelson LD (1987) Glycosphingolipids and antitumor immunity. Biochim Biophys Acta 907:125–143PubMedGoogle Scholar
  18. Dyatlovitskaya EV, Koroleva AB, Suskova VS, Rozynov B, Bergelson LD (1991) Influence of ganglioside GM3 and its breakdown products on lymphoblastic transformation and T-suppressor activity. Eur J Biochem 199:643–646PubMedCrossRefGoogle Scholar
  19. Faulk WP, Temple A (1976) Distribution of beta-2 microglobulin and HLA in chorionic villi of human placentae. Nature 262:799–802PubMedCrossRefGoogle Scholar
  20. Fazakerley JK, Southern P, Bloom F, Buchmeier MJ (1991) High resolution in situ hybridization to determine the cellular distribution of lymphocytic choriomeningitis virus RNA in the tissues of persistently infected mice: relevance to arenavirus disease and mechanisms of viral persistence. J Gen Virol 72:1611–1625PubMedCrossRefGoogle Scholar
  21. Feltner DE, Cooper M, Weber J, Israel MA, Thiele CJ (1989) Expression of class I histocompatibility antigens in neuroectodermal tumors is independent of the expression of a transfected neuroblastoma myc gene. J Immunol 143:4292–4299PubMedGoogle Scholar
  22. Ferry BL, Sargent IL, Starkey PM, Redman CWG (1991) Cytotoxic activity against trophoblast and choriocarcinoma cells of LGL from human early pregnancy decidua. Cell Immunol 132:140–149PubMedCrossRefGoogle Scholar
  23. Fontana A, Fierz W, Wekerle H (1984) Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 307:273–276PubMedCrossRefGoogle Scholar
  24. Geraghty DE, Koller BH, Orr HT (1987) A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proc Natl Acad Sci USA 84:9145–9149PubMedCrossRefGoogle Scholar
  25. Gogate N, Swoveland P, Yamabe T, Verma L, Woyciechowska J, Tamowska-Dziduszko E, Dymecki J, Dhib-Jalbut S (1996) Major histocompatibility complex class I expression on neurons in subacute sclerosing panencephalitis and experimental subacute measles encephalitis. J Neuropathol Exp Neurol 55:435–443PubMedCrossRefGoogle Scholar
  26. Goldstein GW, Betz AL (1986) The blood-brain barrier. Sci Am 155:74–83CrossRefGoogle Scholar
  27. Gombold J, Weiss S (1992) Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system. Microb Pathog 13:493–505PubMedCrossRefGoogle Scholar
  28. Gopas J, Itzhaky D, Segev Y, Salzberg S, Trink B, Isakov N, Rager-Zisman B (1992) Persistent measles virus infection enhances major histocompatibility complex class I expression and immunogenicity of murine neuroblastoma cells. Cancer Immunol Immunother 34:313–320PubMedCrossRefGoogle Scholar
  29. Greengard P (1978) Phosphorylated proteins as physiological effectors. Science 199:146–152PubMedCrossRefGoogle Scholar
  30. Guidotti LG, Ando K, Hobbs MV, Ishikawa T, Runkel L, Schreiber RD, Chisari FV (1994) Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci USA 91:3764–3768PubMedCrossRefGoogle Scholar
  31. Hickey WF, Kimura H (1987) Graft-vs.-host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci USA 84:2082–2086PubMedCrossRefGoogle Scholar
  32. Hickey WF, Osborn JP, Kirby WM (1985) Expression of Ia molecules by astrocytes during acute allergic encephalomyelitis in the Lewis rat. Cell Immunol 91:528–535PubMedCrossRefGoogle Scholar
  33. Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260PubMedCrossRefGoogle Scholar
  34. Hseuh F, Walker C, Blackboum D, Levy J (1994) Suppression of HIV replication by CD8+ cell clones derived from HIV-infected and uninfected individuals. Cell Immunol 159:271–279CrossRefGoogle Scholar
  35. Hunt JS, Orr HT (1992) HLA and maternal-fetal recognition. FASEB J 6:2344–2348PubMedGoogle Scholar
  36. Irani DN, Lin K-I, Griffin DE (1996) Brain-derived gangliosides regulate the cytokine production and proliferation of activated T cells. J Immunol 157:4333–4340PubMedGoogle Scholar
  37. Irani DN, Lin K-I, Griffin DE (1997) Regulation of brain-derived T cells during acute central nervous system inflammation. J Immunol 158:2318–2326PubMedGoogle Scholar
  38. Joly E, Oldstone MBA (1992) Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8:1185–1190PubMedCrossRefGoogle Scholar
  39. Joly E, Mucke L, Oldstone MBA (1991) Viral persistence in neurons explained by lack of MHC class I expression. Science 253:1283–1285PubMedCrossRefGoogle Scholar
  40. Keane RW, Tallent MW, Podack ER (1992) Resistance and susceptibility of neural cells to lysis by cytotoxic lymphocytes and by cytolytic granules. Transplantation 54:520–526PubMedCrossRefGoogle Scholar
  41. Lampson LA, Fisher CA (1984) Weak HLA and β2-microglobulin expression of neuronal cell lines can be modulated by interferon. Proc Natl Acad Sci USA 81:6476–6480PubMedCrossRefGoogle Scholar
  42. Lampson LA, Hickey WF (1986) Monoclonal antibody analysis of MHC expression in human brain biopsies: tissue ranging from “histologically normal” to that showing different levels of glial tumor involvement. J Immunol 136:4054–4062PubMedGoogle Scholar
  43. Lampson LA, Fisher CA, Whelan JP (1983) Striking paucity of HLA-A, B, C and B2 microglobulin on human neuroblastoma cell lines. J Immunol 130:2471–2478PubMedGoogle Scholar
  44. Lassmann, H, Rossler K, Zimprich F, Vass K (1991) Expression of adhesion molecules and histocompatibility antigens at the blood-brain barrier. Brain Pathol 1:115–123PubMedCrossRefGoogle Scholar
  45. Lenardo M, Rustgi AK, Schievella AR, Bernards R (1989) Suppression of MHC class I gene expression by N-myc through enhancer inactivation. EMBO J 8:3351–3355PubMedGoogle Scholar
  46. Liao N-S, Bix M, Zijlstra M, Jaenisch R, Raulet D (1991) MHC class I deficiency; susceptibility to natural killer (NK) cells and impaired NK activity. Science 253:199–202PubMedCrossRefGoogle Scholar
  47. Ludwig H, Bode L, Gosztonyi G (1988) Boma disease: a persistent viral infection of the central nervous system. Prog Med Virol 35:107–120PubMedGoogle Scholar
  48. Maehlen J, Daa Schröder H, Klareskog L, Olsson T, Kristensson K (1988) Axotomy induces MHC class I antigen expression on rat nerve cells. Neurosci Lett 92:8–13PubMedCrossRefGoogle Scholar
  49. Maehlen J, Nennesmo I, Olsson A-B, Olsson T, Daa Schröder H, Kristensson (1989) Peripheral nerve injury causes transient expression of MHC class I antigens in rat motor neurons and skeletal muscles. Brain Res 481:368–372PubMedCrossRefGoogle Scholar
  50. Main EK, Lampson LA, Hart MK, Kombluth J, Wilson DB (1985) Human neuroblastoma lines are susceptible to lysis by natural killer cells but not cytotoxic T lymphocytes. J Immunol 135:242–246PubMedGoogle Scholar
  51. Main EK, Monos DS, Lampson LA (1988) IFN-treated neuroblastoma cell lines remain resistant to T cell-mediated allo-killing, and susceptible to non-MHC-restricted cytotoxicity. J Immunol 141:2943–2950PubMedGoogle Scholar
  52. Mason DW, Charleton HM, Jones AJ, Lavy CBD, Puklavek M, Simmonds SJ (1986) The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19:685–694PubMedCrossRefGoogle Scholar
  53. Massa PT, Ozato K, McFarlin DE (1993) Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes, and neurons. GLIA 8:201207CrossRefGoogle Scholar
  54. Miller CA, Carrigan DR (1982) Reversible repression and activation of measles virus infection in neural cells. Proc Natl Acad Sci USA 79:1629–1633PubMedCrossRefGoogle Scholar
  55. Mucke L, Oldstone MBA (1992) The expression of major histocompatibility complex (MHC) class I antigens in the brain differs markedly in acute and persistent infections with lymphocytic choriomeningitis virus (LCMV). J Neuroimmunol 36:193–198PubMedCrossRefGoogle Scholar
  56. Murphy C, Nikodem D, Howcroft K, Weissman JD, Singer DS (1996) Active repression of major histocompatibility complex class I genes in a human neuroblastoma cell line. J Biol Chem 271:30992–30999PubMedCrossRefGoogle Scholar
  57. Narayan O, Herzog S, Feses K, Scheefers H, Rott R (1983) Behavioral disease in rats caused by immunopathological response to persistent Borna virus infection in the brain. Science 220:1401–1404PubMedCrossRefGoogle Scholar
  58. Neumann H, Cavali A, Jenne DE, Wekerle H (1995) Induction of MHC class I genes in neurons. Science 269:549–552PubMedCrossRefGoogle Scholar
  59. Neumann H, Schmidt H, Cavali A, Jenne D, Wekerle H (1997) Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-γ and tumor necrosis factor (TNF)-a. J Exp Med 185:305–316PubMedCrossRefGoogle Scholar
  60. Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H (1996) Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA 93:4398–4402PubMedCrossRefGoogle Scholar
  61. OMalley MB, MacLeish PR (1993) Induction of class I major histocompatibility complex antigens on adult primate retinal neurons. J Neuroimmunol 43:45–58CrossRefGoogle Scholar
  62. Pearce BD, Hobbs MV, McGraw TS, Buchmeier MJ (1994) Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. J Virol 68:5483–5495PubMedGoogle Scholar
  63. Pereira RA, Tscharke DC, Simmons A (1994) 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. J Exp Med 180:841–850PubMedCrossRefGoogle Scholar
  64. Planz O, Bilzer T, Sobbe M, Stitz L (1993) Lysis of major histocompatibility complex class I-bearing cells in Boma disease virus-induced degenerative encephalopathy. J Exp Med 178:163–174PubMedCrossRefGoogle Scholar
  65. Rail GF, Oldstone MBA (1995) Virus-neuron-cytotoxic T lymphocyte interactions. Curr Top Microbiol Immunol 202:261–273CrossRefGoogle Scholar
  66. Rail GF, Mucke L, Oldstone MBA (1995) Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo. J Exp Med 182:1201–1212CrossRefGoogle Scholar
  67. Rapoport SI (1976) Blood-brain barrier in physiology and medicine. Raven, New YorkGoogle Scholar
  68. Rensing-Ehl A, Malipiero U, Irmler M, Tschopp J, Constam D, Fontana A (1996) Neurons induced to express major histocompatibility complex class I antigen are killed via the perforin and not the Fas (APO-1/CD95) pathway. Eur J Immunol 26:2271–2274PubMedCrossRefGoogle Scholar
  69. Rodriguez M, Buchmeier MJ, Oldstone MBA, Lampert PW (1983) Ultrastructural localization of viral antigens in the CNS of mice persistently infected with lymphocytic choriomeningtitis virus (LCMV). Am J Pathol 110:95–100PubMedGoogle Scholar
  70. Sanders SK, Giblin PA, Kavathas P (1991) Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class I molecule on cytotrophoblasts. J Exp Med 174:737–740PubMedCrossRefGoogle Scholar
  71. Schijns VE, Van derNeut R, Haagmans BL, Bar DR, Schellekens H, Horzinek MC (1991) Tumour necrosis factor-alpha, interferon-gamma and interferon-beta exert antiviral activity in nervous tissue cells. J Gen Virol 72:809–815PubMedCrossRefGoogle Scholar
  72. Sedgwick JD, Dömes R (1991) The immune system response to viral infection of the CNS. Neurosciences 3:93–100Google Scholar
  73. Simmons A (1989) H-2-linked genes influence the severity of herpes simplex virus infection of the peripheral nervous system. J Exp Med 169:1503–1507PubMedCrossRefGoogle Scholar
  74. Simmons A, Tscharke DC (1992) Anti-CD8 impairs clearance of herpes simplex virus from the peripheral nervous system: implications for the fate of virally infected neurons. J Exp Med 175:1337–1344PubMedCrossRefGoogle Scholar
  75. Sobel RA, Ames MB (1988) Major histocompatibility complex molecule expression in the human central nervous system: immunohistochemical analysis of 40 patients. J Neuropathol Exp Neurol 47:19–28PubMedCrossRefGoogle Scholar
  76. Spriggs MK (1996) One step ahead of the game: viral immunomodulatory molecules. Annu Rev Immunol 14:101–130PubMedCrossRefGoogle Scholar
  77. Stanwick TL, Anderson RW, Nahmias AJ (1977) Interaction between cyclic nucleotides and herpes simplex viruses: productive infection. Infect Immun 18:342–347PubMedGoogle Scholar
  78. Ting JP-Y, Masafumi T, Macchi M, Frelinger J (1987) The expression and detection of MHC class I antigens on murine neuroblastoma and ependymoblastoma lines. J Neuroimmunol 14:87–98PubMedCrossRefGoogle Scholar
  79. Tyor WR, Moensch TR, Griffin DE (1989) Characterization of the local and systemic B cell response of normal and athymic nude mice with Sindbis virus encephalitis. J Neuroimmunol 24:207–215PubMedCrossRefGoogle Scholar
  80. vant Veer LJ, Beijersbergen RL, Bernards R (1993) N-myc suppresses major histocompatibility complex class I gene expression through down-regulation of the p50 subunit of NF-kB. EMBO J 12:195–200Google Scholar
  81. Versteeg R, Van Der Minne C, Plomp A, Sijts A, Van Leeuwen A, Schrier P (1990) N-myc expression switched off and class I human leukocyte antigen expression switched on after somatic cell fusion of neuroblastoma cells. Mol Cell Biol 10:5416–5423PubMedGoogle Scholar
  82. Vince GS, Johnson PM (1995) Matemo-fetal immunobiology in normal pregnancy and its possible failure in recurrent spontaneous abortion? Hum Reprod 10:107–113PubMedGoogle Scholar
  83. Voland JR, Becker C, Hooshmand F (1994) Overexpression of class I MHC in murine trophoblast and increased rates of spontaneous abortion. In: Hunt JS (ed) Immunobiology of reproduction. Springer, Berlin Heidelberg New York, pp 214–235CrossRefGoogle Scholar
  84. Ward LA, Massa PT (1995) Neuron-specific regulation of major histocompatibility complex class I, interferon-ß, and anti-viral state genes. J Neuroimmunol 58:145–155PubMedCrossRefGoogle Scholar
  85. Weissman J, Singer DS (1991) A complex regulatory element associated with a major histocompatibility complex class I gene consists of both a silencer and an enhancer. Mol Cell Biol 11:4217–4227PubMedGoogle Scholar
  86. Wekerle H, Linington C, Lassmann H, Meyermann R (1986) Cellular immune reactivity within the CNS. TINS June, pp271–277Google Scholar
  87. Wekerle H, Engelhardt B, Risau W, Meyermann R (1991) Interaction of T lymphocytes with cerebral endothelial cells in vitro. Brain Pathol 1:107–114PubMedCrossRefGoogle Scholar
  88. Weller RO, Engelhardt B, Phillips MJ (1996) Lymphocyte targeting of the central nervous system: areview of afferent and efferent CNS-immune pathways. Brain Pathol 6:275–288PubMedCrossRefGoogle Scholar
  89. Whelan JP, Lampson LA (1985) Expression of MHC class I molecules in normal brain, area postrema and olfactory epithelium. Soc Neurosci 11:1105 (abstr 319.1)Google Scholar
  90. Wiegandt H (1971) Glycosphingolipids. Adv Lipid Res 9:2–49Google Scholar
  91. Wong GHW, Bartlett PF, Clark-Lewis I, Battye F, Schrader JW (1984) Inducible expression of H-2 and la antigens on brain cells. Nature 310:688–691PubMedCrossRefGoogle Scholar
  92. Wood GW (1994) Is restricted antigen presentation the explanation for fetal allograft survival? Immunol Today 15:15–18PubMedCrossRefGoogle Scholar
  93. Yamada S, DePasquale M, Patlak SC, Cserr HF (1991) Albumin outflow into deep cervical lymph from different regions of rabbit brain. Am J Physiol 261 :H1197-H1204PubMedGoogle Scholar
  94. Yoffey JM, Courtice FC (1970) In lymphatics, lymph and the lymphomyeloid complex. Academic, New York, pp 309–314Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Glenn F. Rall
    • 1
  1. 1.Department of Basic Science, Divisions of Virology and ImmunologyThe Fox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations