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.
Highlights
Classical major histocompatability complex class I (MHCI) Ia molecules play a central role in immune surveillance
Based on our previous finding that picomolar levels of recombinant major histocompatibility class I (MHCI) monomers inhibited retina ganglion cells (RGCs) neurite outgrowth in vitro [17], we hypothesized that the diffusible inhibitory factor from neuron-specific enolase (NSE)-Db thalami was soluble forms of MHCI (sMHCI)
The elevated neuronal MHCI expression in NSE-Db mice is associated with lower levels of synaptic markers and fewer neurons in some regions of their hippocampus, as well as a smaller area of contralateral retina projections in their dLGN [19]
Summary
Classical major histocompatability complex class I (MHCI) Ia molecules play a central role in immune surveillance. MHCI on the cell surface is screened by CD82 T cells using T cell receptors that were generated by gene rearrangement to identify cells expressing foreign antigens. SMHCI is generated by 1) the shedding of intact MHCI molecules (which contain the full-length heavy chain with its transmembrane segment and cytoplasmic tail [9,10]); 2) an alternative RNA splicing pathway which deletes the heavy chain’s exon 5 which encodes its transmembrane domain [11,12], and 3) by the action of intracellular or extracellular proteases which cleave the heavy chain from its transmembrane anchor [7,8,10]. SMHCI has no known biological function under natural physiological conditions
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