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.

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

“…The loss of IL-12, was accompanied by a global hyperinflammatory transcriptomic signature in both neurons and oligodendrocytes, including genes linked to antigen presentation (for example, B2m) and type 1 signature (for example, Stat1) indicating pathogenic processes that further potentiate inflammation 39 . Neuronal MHC class I expression mediates a broad repertoire of functions in the steady-state CNS 46 , while the upregulation of MHC class I and Stat1 renders neurons prone to CD8 + cytotoxic T cell-mediated degeneration 42 and impedes CNS repair 47 , suggesting increased neuronal vulnerability in the absence of IL-12. Conversely, a recent report suggested a detrimental role of IL-12 in Alzheimer's disease-like disease pathology 12 .…”