The Murine Family of Gut-Restricted Class Ib MHC Includes Alternatively Spliced Isoforms of the Proposed HLA-G Homolog, “Blastocyst MHC”

Abstract

The gastrointestinal tract is populated by a multitude of specialized immune cells endowed with receptors for classical (class Ia) and nonclassical (class Ib) MHC proteins. To identify class I products that engage these receptors and impact immunity/tolerance, we studied gut-transcribed class Ib loci and their polymorphism in inbred, outbred, and wild-derived mice. Intestinal tissues enriched in epithelial cells contained abundant transcripts of ubiquitously expressed and preferentially gut-restricted Q and T class I loci. The latter category included the “blastocyst Mhc” gene, H2-Bl, and its putative paralog, Tw5. Expression of H2-Bl was previously detected only at the maternal/fetal interface, where it was proposed to induce immune tolerance via interactions with CD94/NKG2A receptors. Analysis of coding region polymorphism performed here revealed two major alleles of H2-Bl with conserved residues at positions critical for class I protein folding and peptide binding. Both divergent alleles are maintained in outbred and wild mice under selection for fecundity and pathogen resistance. Surprisingly, we found that alternative splicing of H2-Bl mRNA in gut tissues is prevalent and allele-specific. It leads to strain-dependent expression of diverse repertoires of canonical and noncanonical transcripts that may give rise to distinct ligands for intestinal NK cell, T cell, and/or intraepithelial lymphocyte receptors.

Differential brain transcriptome of β4 nAChR subunit-deficient mice: is it the effect of the null mutation or the background strain?

“…Differential expression of alternative spliced transcripts between mouse strains was previously detected. For example, differential alternative splicing of H2-Bl gene, a member of the MHC class Ib, was identified in the gut of inbred, outbred, and wild-derived mouse strains (20). Another example is the strain-specific alternative splicing of Pas1c1 gene, which might be the result of a polymorphism in the 3Ј-acceptor splice site of the alternatively spliced exon (51).…”

Expression and alternative splicing of classical and nonclassical MHCI genes in the hippocampus and neuromuscular junction

“…However, little is known about the specific MHCI genes that mediate the newly-discovered neuronal functions of MHCI. Of the roughly twenty-one nonclassical MHCI genes that are known to be transcribed (Guidry and Stroynowski, 2005; Ohtsuka et al, 2008), we detected sixteen in the nervous system ( Q1, Q4, Q5, Q6, Q7, Q10, T5, T7, T10, T11, T15, T22, T23, T24, M2, and M3 ). We also detected both classical MHCI genes found in C57Bl/6 mice ( K and D), as well as three MHCI-like genes (FcRn, MR1, and Cd1d1).…”

“…Nonclassical MHCI genes show relatively low polymorphism and more restricted expression patterns relative to classical MHCI genes. At least 21 nonclassical MHCI genes are transcribed in C57Bl/6 mice (Guidry and Stroynowski, 2005; Ohtsuka et al, 2008). The mouse and human genomes also contain several MHCI-like genes, which encode proteins that are structurally related to MHCI proteins, but are encoded outside the MHCI gene region.…”

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

“…Exon 7 is not transcribed and exon 8 is the 3' UTR region (Gonzalez, Rebmann et al, 2012). Seven different isoforms of human HLA-G are currently known and the mouse homolog (H2-Bl) can be alternatively spliced into at least 3 different isoforms (Guidry andStroynowski, 2005, Amiot, Vu et al, 2015). Here I have used the mouse isoforms most similar to human HLA-G1 (referred to as Membrane Bound (M)) and most similar to human HLA-G5 (referred to as and discovered that transduced ENVY hESC cells exhibited a normal karyotype with the exception of a missing X chromosome 45,X-X.…”