A Potential Role for Shed Soluble Major Histocompatibility Class I Molecules as Modulators of Neurite Outgrowth

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.

Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

“…We previously showed that recombinant self- (but not non-self) MHCI monomers, as well as soluble MHCI that was shed from neurons, could inhibit overall neurite outgrowth from cultured retina explants (Escande-Beillard et al, 2010; Washburn et al, 2011). To further analyze the effects of these closed MHCI conformers on neurite outgrowth we incubated wildtype E15 hippocampal cultures with a self-MHCI monomer, or a non-self MHCI monomer (200 pM) (Fig.…”

“…Our previous studies showed that low levels of recombinant self-MHCI monomers, or soluble MHCI that was shed from neurons, inhibited neurite outgrowth from cultured embryonic retinas (Escande-Beillard et al, 2010; Washburn et al, 2011). Based on this, we anticipated that genetically reduced neuronal MHCI expression would promote neuritogenesis, while genetically increased neuronal MHCI expression would inhibit neuritogenesis.…”

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

“…Although MHC class I is best-known for its role in adaptive immunity, MHC class I also has important roles in the normal, healthy developing and adult brain (e.g., Huh et al 2000;Loconto et al 2003;Leinders-Zufall et al 2004;Goddard et al 2007;Datwani et al 2009;Glynn et al 2011;Washburn et al 2011;Bilousova et al 2012;Chacon and Boulanger 2013; for reviews, see Boulanger et al 2001;Boulanger and Shatz 2004;Boulanger 2009;McAllister and van de Water 2009;Shatz 2009;Elmer and McAllister 2012). MHC class I mRNA is highly expressed in sites of ongoing adult plasticity, including adult hippocampus (Corriveau et al 1998;Huh et al 2000), where it is present in dendrites of CA1 pyramidal neurons (Zhong et al 2006).…”

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

“…However, a growing number of studies have identified unexpected, nonimmune roles for MHC class I in the brain (e.g. (Chacon and Boulanger, 2013;Datwani et al, 2009;Elmer et al, 2013;Glynn et al, 2011;Goddard et al, 2007;Huh et al, 2000;Lee et al, 2014;Leinders-Zufall et al, 2014;Loconto et al, 2003;McConnell et al, 2009;Needleman et al, 2010;Nelson et al, 2013;Washburn et al, 2011;Wu et al, 2010;Zohar et al, 2008)). …”

“…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).…”