New Roles for MHC Class I Immune Molecules in the Healthy and Diseased Nervous System

Abstract

Proteins of the major histocompatibility complex class I (MHC class I) are best known for their central role in the immune response. However, accumulating evidence shows that MHC class I proteins also have nonimmune roles in the healthy nervous system. MHC class I is expressed by developing and adult neurons, and is required for the proper establishment, function and modification of synaptic connections. The newly discovered, critical functions of MHC class I in the healthy nervous system suggest that MHC class I could directly link the immune response to changes in brain structure and function in diverse neurological disorders.

Key Concepts:

  • MHC class I is expressed by developing and mature neurons in the healthy nervous system.

  • Endogenous MHC class I limits neurite outgrowth, limits synapse density and promotes synapse elimination in multiple brain regions.

  • MHC class I limits synaptic transmission mediated by NMDA‐type glutamate receptors in the hippocampus, regulates NMDAR‐dependent synaptic plasticity, and is required for normal NMDAR‐dependent learning and memory.

  • The receptors and signalling pathways that mediate MHC class I's effects on neurons remain largely unknown.

  • Disruption of the nonimmune functions of MHC class I may be an unexpected contributor to diverse neurological disorders.

Keywords: major histocompatibility complex class I; synaptic plasticity; synapse elimination; axon remodelling; synapse density; synaptic transmission, NMDA receptor; PirB

Figure 1.

(a) Schematic of a canonical MHC class I protein, showing the three extracellular alpha domains (in complex with the β2M light chain), the single‐pass transmembrane domain, and the short intracellular tail. Note that the cytoplasmic domain is not drawn to scale. (b) Human and mouse MHC gene families. MHC class I is comprised of both classical (red) and nonclassical (orange) members in humans and in mice. Reprinted with permission from Elmer and McAllister, . © Elsevier.

Figure 2.

Pseudocolored in situ hybridisation shows mRNA encoding three different MHC class I genes in three superimposed, consecutive coronal sections from anterior (left) and (posterior) regions of adult mouse brain. Blue, H2‐Db; red, T22; Green, Qa‐1. Reprinted with permission from Boulanger and Shatz, and Boulanger, . © Elsevier.

Figure 3.

Activity‐dependent refinement of RGC projections into the LGN. Initially (top) axon arbours from both eyes are overlapping. RGC inputs from the two eyes resolve into eye‐specific layers (bottom) through a process of activity‐dependent axon remodelling during development. Reprinted with permission from Boulanger et al., . © Elsevier.

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References

Adelson JD, Barreto GE, Xu L et al. (2012) Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73: 1100–1107.

Atwal JK, Pinkston‐Gosse J, Syken J et al. (2008) PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322: 967–970.

Baudouin SJ, Angibaud J, Loussouarn G et al. (2008) The signaling adaptor protein CD3zeta is a negative regulator of dendrite development in young neurons. Molecular Biology of the Cell 19: 2444–2456.

Bilousova T, Dang H, Xu W et al. (2012) Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization. Journal of Neuroimmunology 247: 1–8.

Bjorkman PJ and Parham P (1990) Structure, function, and diversity of class I major histocompatibility complex molecules. Annual Review of Biochemistry 59: 253–288.

Boulanger LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64(1): 93–109.

Boulanger LM, Huh GS and Shatz CJ (2001) Neuronal plasticity and cellular immunity: shared molecular mechanisms. Current Opinion in Neurobiology 11(5): 568–578.

Boulanger LM and Shatz CJ (2004) Immune signalling in neural development, synaptic plasticity and disease. Nature Reviews Neuroscience 5(7): 521–531.

Brown AS (2006) Prenatal infection as a risk factor for schizophrenia. Schizophrenia Bulletin 32: 200–202.

Brown AS and Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167: 261–280.

Carson MJ, Doose JM, Melchior B, Schmid CD and Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunological Reviews 213: 48–65.

Chacon MA and Boulanger LM (2013) MHC class I protein is expressed by neurons and neural progenitors in mid‐gestation mouse brain. Molecular and Cellular Neuroscience 52: 117–127.

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.

Datwani A, McConnell MJ, Kanold PO et al. (2009) Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron 64: 463–470.

Dixon-Salazar TJ, Fourgeaud L, Tyler CM et al. (2014) MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling. Journal of Neuroscience 34: 11844–11856.

Elmer BM, Estes ML, Barrow SL and McAllister AK (2013) MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease. Journal of Neuroscience 33: 13791–13804.

Elmer BM and McAllister AK (2012) Major histocompatibility complex class I proteins in brain development and plasticity. Trends in Neuroscience 35(11): 649–710.

Escande‐Beillard N, Washburn L, Zekzer D et al. (2010) Neurons preferentially respond to self‐MHC class I allele products regardless of peptide presented. Journal of Immunology 184: 816–823.

Fehlmann M, Chvatchko Y, Brandenburg D, Van Obberghen E and Brossette N (1985a) The subunit structure of the insulin receptor and molecular interactions with major histocompatibility complex antigens. Biochimie 67: 1155–1159.

Fehlmann M, Peyron JF, Samson M et al. (1985b) Molecular association between major histocompatibility complex class I antigens and insulin receptors in mouse liver membranes. Proceedings of the National Academy of Sciences of the USA 82: 8634–8637.

Fourgeaud L, Davenport CM, Tyler CM et al. (2010) MHC class I modulates NMDA receptor function and AMPA receptor trafficking. Proceedings of the National Academy of Sciences of the USA 107: 22278–22283.

Glynn MW, Elmer BM, Garay PA et al. (2011) MHCI negatively regulates synapse density during the establishment of cortical connections. Nature Neuroscience 14: 442–451.

Goddard CA, Butts DA and Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proceedings of the National Academy of Sciences of the USA 104: 6828–6833.

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

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

Jia P, Wang L, Fanous AH et al. (2012) A bias‐reducing pathway enrichment analysis of genome‐wide association data confirmed association of the MHC region with schizophrenia. Journal of Medical Genetics 49: 96–103.

Lee H, Brott BK, Kirkby LA et al. (2014) Synapse elimination and learning rules co‐regulated by MHC class I H2‐D. Nature 509(7499): 195–200.

Leinders‐Zufall T, Ishii T, Chamero P et al. (2014) A family of nonclassical class I MHC genes contributes to ultrasensitive chemodetection by mouse vomeronasal sensory neurons. Journal of Neuroscience 34: 5121–5133.

Letellier M, Willson ML, Gautheron V, Mariani J and Lohof AM (2008) Normal adult climbing fiber monoinnervation of cerebellar Purkinje cells in mice lacking MHC class I molecules. Developmental Neurobiology 68: 997–1006.

Li XC and Raghavan M (2010) Structure and function of major histocompatibility complex class I antigens. Current Opinion in Organ Transplantation 15: 499–504.

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. Experimental Neurology 150: 282–295.

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. Journal of Comparative Neurology 425: 10–23.

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.

McAllister AK (2014) Major histocompatibility complex I in brain development and schizophrenia. Biological Psychiatry 75: 262–268.

McConnell MJ, Huang YH, Datwani A and Shatz CJ (2009) H2‐Kb and H2‐Db regulate cerebellar long‐term depression and limit motor learning. Proceedings of the National Academy of Sciences of the USA 106: 6784–6789.

Needleman LA, Liu XB, El‐Sabeawy F, Jones EG and McAllister AK (2010) MHC class I molecules are present both pre‐ and postsynaptically in the visual cortex during postnatal development and in adulthood. Proceedings of the National Academy of Sciences of the USA 107: 16999–17004.

Nelson PA, Sage JR, Wood SC et al. (2013) MHC class I immune proteins are critical for hippocampus‐dependent memory and gate NMDAR‐dependent hippocampal long‐term depression. Learning and Memory 20: 505–517.

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

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. Proceedings of the National Academy of Sciences of the USA 101: 17843–17848.

Raiker SJ, Lee H, Baldwin KT et al. (2010) Oligodendrocyte‐myelin glycoprotein and Nogo negatively regulate activity‐dependent synaptic plasticity. Journal of Neuroscience: the Official Journal of the Society for Neuroscience 30: 12432–12445.

Salter‐Cid L, Peterson PA and Yang Y (2000) The major histocompatibility complex‐encoded HFE in iron homeostasis and immune function. Immunologic Research 22: 43–59.

Shatz CJ (1990) Competitive interactions between retinal ganglion cells during prenatal development. Journal of Neurobiology 21: 197–211.

Shi J, Levinson DF, Duan J et al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460: 753–757.

Stefansson HRA, Ophoff S, Steinberg OA et al. (2009) Common variants conferring risk of schizophrenia. Nature 460: 744–747.

Stellwagen D and Malenka RC (2006) Synaptic scaling mediated by glial TNF‐alpha. Nature 440: 1054–1059.

Syken J, Grandpre T, Kanold PO and Shatz CJ (2006) PirB restricts ocular‐dominance plasticity in visual cortex. Science 313: 1795–1800.

Syken J and Shatz CJ (2003) Expression of T cell receptor beta locus in central nervous system neurons. Proceedings of the National Academy of Sciences of the USA 100: 13048–13053.

Thams S, Brodin P, Plantman S et al. (2009) Classical major histocompatibility complex class I molecules in motoneurons: new actors at the neuromuscular junction. Journal of Neuroscience 29: 13503–13515.

Thams S, Oliveira A and Cullheim S (2008) MHC class I expression and synaptic plasticity after nerve lesion. Brain Research Reviews 57: 265–269.

Turrigiano GG (2008) The self‐tuning neuron: synaptic scaling of excitatory synapses. Cell 135: 422–435.

Washburn LR, Zekzer D, Eitan S et al. (2011) A potential role for shed soluble major histocompatibility class I molecules as modulators of neurite outgrowth. PLoS One 6: e18439.

Wu ZP, Bilousova T, Escande‐Beillard N et al. (2010) Major histocompatibility complex class I‐mediated inhibition of neurite outgrowth from peripheral nerves. Immunology Letters 135(1–2): 118–123.

Wu ZP, Washburn L, Bilousova TV et al. (2011) Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. Journal of Neuroimmunology 232: 8–16.

Xu HP, Chen H, Ding Q et al. (2010) The immune protein CD3zeta is required for normal development of neural circuits in the retina. Neuron 65: 503–515.

Zohar O, Reiter Y, Bennink JR et al. (2008) Cutting edge: MHC class I‐ly49 interaction regulates neuronal function. Journal of Immunology 180: 6447–6451.

Further Reading

Cullheim S and Thams S (2010) Classic major histocompatibility complex class I molecules: new actors at the neuromuscular junction. Neuroscientist 16(6): 600–607.

Fourgeaud L and Boulanger LM (2010) Role of immune molecules in the establishment and plasticity of glutamatergic synapses. European Journal of Neuroscience 32(2): 207–217.

Shatz CJ (2009) MHC class I: an unexpected role in neuronal plasticity. Neuron 64(1): 40–45.

Thams S and Cullheim S (2009) MHC class I function at the neuronal synapse. In: Hortsch M and Umemori H (eds) The Sticky Synapse: Cell Adhesion Molecules and Their Role in Synapse Formation and Maintenance, pp. 301–320. New York: Springer Science & Business Media.

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Tyler, Carolyn M, and Boulanger, Lisa M(Oct 2014) New Roles for MHC Class I Immune Molecules in the Healthy and Diseased Nervous System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025802]