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


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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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. [doi: 10.1002/9780470015902.a0025802]