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MHC Class I Function at the Neuronal Synapse

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The Sticky Synapse

Abstract

The major histocompatibility complex class I (MHC class I) encodes a family of immune recognition molecules acting as ligands at immune synapses, thereby conveying adaptive and innate immunity. MHC class I proteins are expressed by all nucleated vertebrate cells, including neurons, and can mediate immune clearance of neurotropic viruses in the CNS. Intriguingly, there are now indications for a non-immune role of MHC class I signalling at neuronal synapses. Thus, neuronal MHC class I expression has been linked to synaptic plasticity and the modulation of neuronal functions. Up to this day, two MHC class I receptors have been identified at the neuronal synapse, which provide a molecular basis for MHC class I-dependent signalling across the synapse. Possible clinical implications of MHC class I expression in the CNS are currently being investigated in relation to neurodevelopmental and neurodegenerative diseases, in which synaptic dysfunction is a cardinal feature.

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References

  • Asaka Y, Jugloff DG, Zhang L et al. (2006) Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 21:217–227

    Article  PubMed  CAS  Google Scholar 

  • Becher B, Barker PA, Owens T et al. (1998) CD95-CD95L: can the brain learn from the immune system? Trends Neurosci 21:114–117

    Article  PubMed  CAS  Google Scholar 

  • Bianchin MM, Capella HM, Chaves DL et al. (2004) Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy – PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 24:1–24

    Article  PubMed  CAS  Google Scholar 

  • Bien CG, Bauer J, Deckwerth TL et al. (2002) Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann Neurol 51:311–318

    Article  PubMed  CAS  Google Scholar 

  • Bilzer T and Stitz L (1994) Immune-mediated brain atrophy. CD8+ T cells contribute to tissue destruction during borna disease. J Immunol 153:818–823

    PubMed  CAS  Google Scholar 

  • Boulanger LM and Shatz CJ (2004) Immune signalling in neural development, synaptic plasticity and disease. Nature Rev 5:521–531

    Article  CAS  Google Scholar 

  • Bryceson YT, Foster JA, Kuppusamy SP et al. (2005) Expression of a killer cell receptor-like gene in plastic regions of the central nervous system. J Neuroimmunol 161:177–182

    Article  PubMed  CAS  Google Scholar 

  • Bryceson YT, March ME, Ljunggren HG et al. (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91

    Article  PubMed  CAS  Google Scholar 

  • Carey BW, Kim DY and Kovacs DM (2007) Presenilin/gamma-secretase and alpha-secretase-like peptidases cleave human MHC Class I proteins. Biochem J 401:121–127

    Article  PubMed  CAS  Google Scholar 

  • Chao HT, Zoghbi HY and Rosenmund C (2007) MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56:58–65

    Article  PubMed  CAS  Google Scholar 

  • Cohen H, Ziv Y, Cardon M et al. (2006) Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J Neurobiol 66:552–563

    Article  PubMed  Google Scholar 

  • Corriveau RA, Huh GS and Shatz CJ (1998) Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505–520

    Article  PubMed  CAS  Google Scholar 

  • de la Salle H, Saulquin X, Mansour I et al. (2002) Asymptomatic deficiency in the peptide transporter associated to antigen processing (TAP). Clin Exp Immunol 128:525–531

    Article  PubMed  Google Scholar 

  • Degreef G, Ashtari M, Bogerts B et al. (1992) Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Arch Gen Psychiatry 49:531–537

    PubMed  CAS  Google Scholar 

  • Demaria S and Bushkin Y (2000) Soluble HLA proteins with bound peptides are released from the cell surface by the membrane metalloproteinase. Hum Immunol 61:1332–1338

    Article  PubMed  CAS  Google Scholar 

  • Dulac C and Axel R (1995) A novel family of genes encoding putative pheromone receptors in mammals. Cell 83:195–206

    Article  PubMed  CAS  Google Scholar 

  • Dulac C and Torello AT (2003) Molecular detection of pheromone signals in mammals: from genes to behaviour. Nature Rev 4:551–562

    Article  CAS  Google Scholar 

  • Dustin ML and Colman DR (2002) Neural and immunological synaptic relations. Science 298:785–789

    Article  PubMed  CAS  Google Scholar 

  • Flajnik MF and Kasahara M (2001) Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15:351–362

    Article  PubMed  CAS  Google Scholar 

  • Foster JA, Quan N, Stern EL et al. (2002) Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models. J Neuroimmunol 131:83–91

    Article  PubMed  CAS  Google Scholar 

  • Galea I, Bechmann I and Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18

    Article  PubMed  CAS  Google Scholar 

  • Giuliani F, Goodyer CG, Antel JP et al. (2003) Vulnerability of human neurons to T cell-mediated cytotoxicity. J Immunol 171:368–379

    PubMed  CAS  Google Scholar 

  • Goddard CA, Butts DA and Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci USA 104:6823–6833

    Article  Google Scholar 

  • Griffin DE (2003) Immune responses to RNA-virus infections of the CNS. Nat Rev Immunol 3:493–502

    Article  PubMed  CAS  Google Scholar 

  • Guy J, Hendrich B, Holmes M et al. (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326

    Article  PubMed  CAS  Google Scholar 

  • Held W and Mariuzza RA (2008) Cis interactions of immunoreceptors with MHC and non-MHC ligands. Nat Rev Immunol 8:269–278

    Article  PubMed  CAS  Google Scholar 

  • Herrada G and Dulac C (1997) A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90:763–773

    Article  PubMed  CAS  Google Scholar 

  • Hoftberger R, Aboul-Enein F, Brueck W et al. (2004) Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol (Zurich, Switzerland) 14:43–50

    CAS  Google Scholar 

  • Horwitz MS, Evans CF, Klier FG et al. (1999) Detailed in vivo analysis of interferon-gamma induced major histocompatibility complex expression in the central nervous system: astrocytes fail to express major histocompatibility complex class I and II molecules. Lab Invest 79:235–242

    Google Scholar 

  • Huh GS, Boulanger LM, Du H et al. (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159

    Article  PubMed  CAS  Google Scholar 

  • Ishii T, Hirota J and Mombaerts P (2003) Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr Biol 13:394–400

    Article  PubMed  CAS  Google Scholar 

  • Ishii T and Mombaerts P (2008) Expression of nonclassical class I major histocompatibility genes defines a tripartite organization of the mouse vomeronasal system. J Neurosci 28:2332–2341

    Article  PubMed  CAS  Google Scholar 

  • Janeway C and Travers P (1997) Immunobiology: the immune system in health and disease. Current Biology; Churchill Livingstone, Edingurgh; Garland Publication, London, San Francisco, New York

    Google Scholar 

  • Karre K, Ljunggren HG, Piontek G et al. (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–678

    Article  PubMed  CAS  Google Scholar 

  • Keshavan MS, Anderson S and Pettegrew JW (1994) Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J Psychiatr Res 28:239–265

    Article  PubMed  CAS  Google Scholar 

  • Keverne EB (1999) The vomeronasal organ. Science 286:716–720

    Article  PubMed  CAS  Google Scholar 

  • Kimura T and Griffin DE (2000) The role of CD8(+) T cells and major histocompatibility complex class I expression in the central nervous system of mice infected with neurovirulent Sindbis virus. J Virol 74:6117–6125

    Article  PubMed  CAS  Google Scholar 

  • Leinders-Zufall T, Brennan P, Widmayer P et al. (2004) MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306:1033–1037

    Article  PubMed  CAS  Google Scholar 

  • Leinders-Zufall T, Lane AP, Puche AC et al. (2000) Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Nature 405:792–796

    Article  PubMed  CAS  Google Scholar 

  • Lidman O, Olsson T and Piehl F (1999) Expression of nonclassical MHC class I (RT1-U) in certain neuronal populations of the central nervous system. Euro J Neurosci 11:4468–4472

    Article  CAS  Google Scholar 

  • Linda H, Hammarberg H, Cullheim S et al. (1998) Expression of MHC class I and beta2-microglobulin in rat spinal motoneurons: regulatory influences by IFN-gamma and axotomy. Exp Neurol 150:282–295

    Article  PubMed  CAS  Google Scholar 

  • Linda H, Hammarberg H, Piehl F et al. (1999) Expression of MHC class I heavy chain and beta2-microglobulin in rat brainstem motoneurons and nigral dopaminergic neurons. J Neuroimmunol 101:76–86

    Article  PubMed  CAS  Google Scholar 

  • Linda H, Shupliakov O, Ornung G et al. (2000) Ultrastructural evidence for a preferential elimination of glutamate-immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy. J Comp Neurol 425:10–23

    Article  PubMed  CAS  Google Scholar 

  • Ljunggren HG and Karre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244

    Article  PubMed  CAS  Google Scholar 

  • Ljunggren HG, Stam NJ, Ohlen C et al. (1990) Empty MHC class I molecules come out in the cold. Nature 346:476–480

    Article  PubMed  CAS  Google Scholar 

  • Loconto J, Papes F, Chang E et al. (2003) Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112:607–618

    Article  PubMed  CAS  Google Scholar 

  • MacKay PA, Leibundgut-Landmann S, Koch N et al. (2006) Circulating, soluble forms of major histocompatability complex antigens are not exosome-associated. Euro J Immunol 36:2875–2884

    Article  Google Scholar 

  • Medana I, Martinic MA, Wekerle H et al. (2001) Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 159:809–815

    PubMed  CAS  Google Scholar 

  • Medana IM, Gallimore A, Oxenius A et al. (2000) MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Euro J Immunol 30:3623–3633

    Article  CAS  Google Scholar 

  • Medrihan L, Tantalaki E, Aramuni G et al. (2008) Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J Neurophysiol 99:112–121

    Article  PubMed  CAS  Google Scholar 

  • Mendez-Fernandez YV, Johnson AJ, Rodriguez M et al. (2003) Clearance of Theiler’s virus infection depends on the ability to generate a CD8+ T cell response against a single immunodominant viral peptide. Euro J Immunol 33:2501–2510

    Article  CAS  Google Scholar 

  • Miralves J, Magdeleine E, Kaddoum L et al. (2007) High Levels of MeCP2 Depress MHC Class I Expression in Neuronal Cells. PLoS ONE 2:e1354

    Article  PubMed  CAS  Google Scholar 

  • Muller D, Koller BH, Whitton JL et al. (1992) LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science 255:1576–1578

    Article  PubMed  CAS  Google Scholar 

  • Neumann H, Cavalie A, Jenne DE et al. (1995) Induction of MHC class I genes in neurons. Science 269:549–552

    Article  PubMed  CAS  Google Scholar 

  • Neumann H, Schmidt H, Cavalie A et al. (1997) Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med 185:305–316

    Article  PubMed  CAS  Google Scholar 

  • Niedermann G, Butz S, Ihlenfeldt HG et al. (1995) Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. Immunity 2:289–299

    Article  PubMed  CAS  Google Scholar 

  • Niedermann G, Grimm R, Geier E et al. (1997) Potential immunocompetence of proteolytic fragments produced by proteasomes before evolution of the vertebrate immune system. J Exp Med 186:209–220

    Article  PubMed  CAS  Google Scholar 

  • Oliveira AL, Thams S, Lidman O et al. (2004) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci USA 101:17843–17848

    Article  PubMed  CAS  Google Scholar 

  • Olson R, Dulac C and Bjorkman PJ (2006) MHC homologs in the nervous system – they haven’t lost their groove. Curr Opin Neurobiol 16:351–357

    Article  PubMed  CAS  Google Scholar 

  • Olson R, Huey-Tubman KE, Dulac C et al. (2005) Structure of a pheromone receptor-associated MHC molecule with an open and empty groove. PLoS Biol 3:e257

    Article  PubMed  CAS  Google Scholar 

  • Ornung G, Ottersen OP, Cullheim S et al. (1998) Distribution of glutamate-, glycine- and GABA-immunoreactive nerve terminals on dendrites in the cat spinal motor nucleus. Exp Brain Res 118:517–532

    Article  PubMed  CAS  Google Scholar 

  • Ornung G, Shupliakov O, Linda H et al. (1996) Qualitative and quantitative analysis of glycine- and GABA-immunoreactive nerve terminals on motoneuron cell bodies in the cat spinal cord: a postembedding electron microscopic study. J Comp Neurol 365:413–426

    Article  PubMed  CAS  Google Scholar 

  • Ornung G, Shupliakov O, Ottersen OP et al. (1994) Immunohistochemical evidence for coexistence of glycine and GABA in nerve terminals on cat spinal motoneurones: an ultrastructural study. Neuroreport 5:889–892

    Article  PubMed  CAS  Google Scholar 

  • Peng J, Xie L, Stevenson FF et al. (2006) Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration. J Neurosci 26:11644–11651

    Article  PubMed  CAS  Google Scholar 

  • Redwine JM, Buchmeier MJ and Evans CF (2001) In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. Am J Pathol 159:1219–1224

    PubMed  CAS  Google Scholar 

  • Rivera-Quinones C, McGavern D, Schmelzer JD et al. (1998) Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nat Med 4:187–193

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez M, Zoecklein LJ, Howe CL et al. (2003) Gamma interferon is critical for neuronal viral clearance and protection in a susceptible mouse strain following early intracranial Theiler’s murine encephalomyelitis virus infection. J Virol 77:12252–12265

    Article  PubMed  CAS  Google Scholar 

  • Rolleke U, Flugge G, Plehm S et al. (2006) Differential expression of major histocompatibility complex class I molecules in the brain of a New World monkey, the common marmoset (Callithrix jacchus). J Neuroimmunol 176:39–50

    Article  PubMed  CAS  Google Scholar 

  • Roumier A, Bechade C, Poncer JC et al. (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 24:11421–11428

    Article  PubMed  CAS  Google Scholar 

  • Sessa G, Podini P, Mariani M et al. (2004) Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Euro J Neurosci 20:2617–2628

    Article  Google Scholar 

  • Smrt RD, Eaves-Egenes J, Barkho BZ et al. (2007) Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis 27:77–89

    Article  PubMed  CAS  Google Scholar 

  • Syken J, Grandpre T, Kanold PO et al. (2006) PirB restricts ocular-dominance plasticity in visual cortex. Science 313:1795–1800

    Article  PubMed  CAS  Google Scholar 

  • Syken J and Shatz CJ (2003) Expression of T cell receptor beta locus in central nervous system neurons. Proc Natl Acad Sci USA 100:13048–13053

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Rochford CD and Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657

    Article  PubMed  CAS  Google Scholar 

  • Taniguchi H, Gollan L, Scholl FG et al. (2007) Silencing of neuroligin function by postsynaptic neurexins. J Neurosci 27:2815–2824

    Article  PubMed  CAS  Google Scholar 

  • Zhong J, Zhang T and Bloch LM (2006) Dendritic mRNAs encode diversified functionalities in hippocampal pyramidal neurons. BMC Neurosci 7:17

    Article  PubMed  CAS  Google Scholar 

  • Zinkernagel RM and Doherty PC (1974) Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251:547–548

    Article  PubMed  CAS  Google Scholar 

  • Ziv Y, Ron N, Butovsky O et al. (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275

    Article  PubMed  CAS  Google Scholar 

  • Zoghbi HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302:826–830

    Article  PubMed  CAS  Google Scholar 

  • Zohar O, Reiter Y, Bennink JR et al. (2008) Cutting edge: MHC class I-ly49 interaction regulates neuronal function. J Immunol 180:6447–6451

    PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dr. Yenan T. Bryceson at the Karolinska Institutet for helpful comments on the manuscript and Dr. Carla Shatz at Stanford University for permission to use a figure from one of her publications.

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  1. Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden

    Sebastian Thams & Staffan Cullheim

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Correspondence to Sebastian Thams .

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    Thams, S., Cullheim, S. (2009). MHC Class I Function at the Neuronal Synapse. In: Umemori, H., Hortsch, M. (eds) The Sticky Synapse. Springer, New York, NY. https://doi.org/10.1007/978-0-387-92708-4_14

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