Neurons Preferentially Respond to Self-MHC Class I Allele Products Regardless of Peptide Presented

Abstract

Studies of mice lacking MHC class I (MHC I)-associated proteins have demonstrated a role for MHC I in neurodevelopment. A central question arising from these observations is whether neuronal recognition of MHC I has specificity for the MHC I allele product and the peptide presented. Using a well-established embryonic retina explant system, we observed that picomolar levels of a recombinant self-MHC I molecule inhibited neurite outgrowth. We then assessed the neurobiological activity of a panel of recombinant soluble MHC Is, consisting of different MHC I heavy chains with a defined self- or nonself-peptide presented, on cultured embryonic retinas from mice with different MHC I haplotypes. We observed that self-MHC I allele products had greater inhibitory neuroactivity than nonself-MHC I molecules, regardless of the nature of the peptide presented, a pattern akin to MHC I recognition by some innate immune system receptors. However, self-MHC I molecules had no effect on retinas from MHC I-deficient mice. These observations suggest that neuronal recognition of MHC I may be coordinated with the inherited MHC I alleles, as occurs in the innate immune system. Consistent with this notion, we show that MHC I and MHC I receptors are coexpressed by precursor cells at the earliest stages of retina development, which could enable such coordination.

Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves

“…These recombinant MHCI stocks were used in a separate concurrent study and shown to be biologically active and free of neuroinhibitory toxins [8]. …”

“…Lumbar level DRGs were dissected from E14 C57Bl/6 mice and placed into growth factor reduced (GFR) matrigel matrix (BD Biosciences) with 2.5S NGF (100 ng/ml, Invitrogen), in the presence or absence of the indicated MHCI monomer (500 pM, a concentration previously shown to inhibit neurite outgrowth from RGCs) [8] in an 8-chamber slide on ice (Lab-Tek Chamber slides). The slides were incubated at 37°C for 30-60 minutes to solidify the gel.…”

“…In contrast, the MHCI receptors of NK cells of the innate immune system (e.g., the Ly49 in mice and KIR gene families in humans) are germline-encoded and can recognize one to several MHCI allele products often without specificity for the presented peptide [6,7]. Using a wildtype retina explant system, we showed that picomolar levels of recombinant soluble self-MHCI inhibited neurite outgrowth from retina ganglion cells (RGCs) [8]. Self-MHCI allele products had greater inhibitory neuroactivity than non-self MHCI molecules, regardless of the nature of the peptide presented--a pattern akin to MHCI recognition by some MHCI receptors of the innate immune system receptors [8].…”

“…Using a wildtype retina explant system, we showed that picomolar levels of recombinant soluble self-MHCI inhibited neurite outgrowth from retina ganglion cells (RGCs) [8]. Self-MHCI allele products had greater inhibitory neuroactivity than non-self MHCI molecules, regardless of the nature of the peptide presented--a pattern akin to MHCI recognition by some MHCI receptors of the innate immune system receptors [8]. Interestingly, retinas from MHCI-deficient mice were not affected by recombinant MHCI, suggesting that endogenous MHCI expression was necessary to “educate” neurons to express appropriate MHCI receptors, as occurs during NK cell development.…”

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

“…Experiments with MHC class I-deficient or -overexpressing neurons growing in vitro suggest that MHC class I limits axon outgrowth in retinal explants and cultured dorsal root ganglion neurons (Bilousova et al, 2012;Escande-Beillard et al, 2010;Washburn et al, 2011;Wu et al, 2011). Similarly, anti-MHC class I antibodies promote neurite outgrowth in cultured cortical neurons (Zohar et al, 2008).…”