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

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90024, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2009; 184(2):816-23. DOI: 10.4049/jimmunol.0902159
Source: PubMed


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.

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Available from: Sebastian Joyce, Feb 04, 2014
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    • "In contrast, there was a conspicuous lack of neurite outgrowth from retina explant regions that were proximal to thalamic explants from NSE-Db mice, suggesting that this thalamic tissue released a factor that inhibited nearby neurite outgrowth. Since our previous studies showed that recombinant MHCI monomers (but not heavy chain alone or β2M alone) inhibited neurite outgrowth in vitro [17], we surmised that the NSE-Db thalami were producing sMHCI which inhibited neurite outgrowth from neighboring neurons. Indeed, in other tissues, upregulated MHCI expression leads to increased release of sMHCI [22], [23], [24], [25]. "
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    ABSTRACT: The neurobiological activities of classical major histocompatibility class I (MHCI) molecules are just beginning to be explored. To further examine MHCI's actions during the formation of neuronal connections, we cultured embryonic mouse retina explants a short distance from wildtype thalamic explants, or thalami from transgenic mice (termed "NSE-Db") whose neurons express higher levels of MHCI. While retina neurites extended to form connections with wildtype thalami, we were surprised to find that retina neurite outgrowth was very stunted in regions proximal to NSE-Db thalamic explants, suggesting that a diffusible factor from these thalami inhibited retina neurite outgrowth. It has been long known that MHCI-expressing cells release soluble forms of MHCI (sMHCI) due to the shedding of intact MHCI molecules, as well as the alternative exon splicing of its heavy chain or the action proteases which cleave off it's transmembrane anchor. We show that the diffusible inhibitory factor from the NSE-Db thalami is sMHCI. We also show that COS cells programmed to express murine MHCI release sMHCI that inhibits neurite outgrowth from nearby neurons in vitro. The neuroinhibitory effect of sMHCI could be blocked by lowering cAMP levels, suggesting that the neuronal MHCI receptor's signaling mechanism involves a cyclic nucleotide-dependent pathway. Our results suggest that MHCI may not only have neurobiological activity in its membrane-bound form, it may also influence local neurons as a soluble molecule. We discuss the involvement of complement proteins in generating sMHCI and new theoretical models of MHCI's biological activities in the nervous system.
    PLoS ONE 03/2011; 6(3):e18439. DOI:10.1371/journal.pone.0018439 · 3.23 Impact Factor
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    • "On the other hand, the possible interspecies differences in function are not surprising. MHCI molecules exhibit a multitude of functions and may, for example, transmit both activating and inhibitory signals in the immune system [7,84]. MHCI proteins are also necessary for immunological synapse formation [85]. "
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    ABSTRACT: Mice deficient in classical major histocompatibility complex class I (MHCI) have aberrations in neurodevelopment. The consequences of upregulated neuronal MHCI expression have not been examined. We found that transgenic C57Bl/6 mice that are engineered to express higher levels of self-D(b) on their CNS neurons have alterations in their hippocampal morphology and retinogeniculate projections, as well as impaired neurorepair responses. Thus, enhanced neuronal classical MHCI expression can lead to aberrations in neural circuitry and neurorepair. These findings complement a growing body of knowledge concerning the neurobiological activities of MHCI and may have potential clinical relevance.
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