The Major Histocompatibility Complex (MHC) is the genetic region that encodes the transplantation antigens or MHC class I (MHC-I) and MHC class II (MHC-II) molecules, which are primarily involved in protecting the body against pathogens.
Class I proteins comprise an alpha (α) polypeptide chain which is a large subunit of 44 kilodaltons (D) molecular weight (MW) that is non-covalently linked with a 12 kD-light chain called β2 microglobulin (β2m) to form a stable cell surface protein. The gene for the β2m is not located in the MHC region. MHC-II proteins are heterodimers composed of an alpha (α) and a beta (β) polypeptide chain. Class II molecules are expressed on professional antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages and B cells. Class II molecules are not expressed on placental trophoblast cells and, therefore, will not be described in detail here.
Classical (MHC-Ia) and Non-classical (MHC-Ib) MHC-I Proteins
MHC-Ia proteins show ubiquitous ex
MHC-Ib genes are monomorphic or oligomorphic and often possess premature stop codons, and/or putative non-classical amino acid motifs (IPI and VPI) in the transmembrane domain. Similar to class Ia genes, most class Ib genes have eight exons which encode the heavy chain. Exon 1 encodes the signal sequence that is cleaved after the newly synthesized protein is targeted into the endoplasmic reticulum (ER). Exons 2, 3 and 4 encode the α1, α2 and α3 domains, which form the extracellular portion of the protein. The transmembrane domain is encoded by exon 5. Exons 6, 7, and sometimes part of exon 8 encode the cytoplasmic domain. In contrast to MHC-Ia proteins, nonclassical class I proteins (MHC-Ib) are expressed in specific tissues and under specific conditions. These proteins often have a truncated cytoplasmic domain. As a result of alternative splicing, these proteins are produced as transmembrane and soluble isoforms. The process of alternative splicing determines the secreted or lipid-linked nature of some class Ib molecules such as HLA-G (HLA-G2) and Qa-2. Alternative splicing of HLA-G or Qa-2 transcripts that eliminates or splices out exon 5, results in only secreted isoforms. In contrast to class Ia molecules which require binding with a light chain or β2-microglobulin (β2m) for their cell-surface ex
Peptide Binding to MHC I Glycoproteins
MHC class I proteins bind peptides from intracellular pathogens and the animal’s own protein-derived peptides. The protein complexes are digested in the cytosol by proteasomes into 8-10 amino acid long peptides. These peptides are accommodated in the peptide-binding cleft formed by the α1 and α2 domains of MHC-I proteins. The N-termini of freshly synthesized MHC-I glycoproteins contain N-linked glycan. N-linked glycans are trimmed by Glucosidases I and II (GlsI/II) to a single terminal glucose residue, which allows the MHC-I protein to interact with chaperon proteins. After this, the first interaction is with calnexin (CNX), which allows β2m to bind with the MHC-I heavy chain. Calreticulin (CRT) then recruits the MHC- protein to the peptide loading complex (PLC). The PLC is formed by the transporter associated with antigen processing (TAP) heterodimer together with other proteins and chaperon molecules. Tapasin, Erp 57, and CRT in association with other chaperons in the PLC help to locate the MHC-I protein to the PLC. Peptides longer than 8-10 amino acids are trimmed by ER aminopeptidases known as “ERAAP/ERAP1 and ERAP2.” Finally, tapasin-mediated editing results in preferential binding of approximately sized peptides in the peptidebinding groove. The MHC-I-peptide complexes then move to the cell surface for recognition by T cell-receptors on CD8+ T lymphocytes.
The Role of MHC Class I Proteins in Cattle Reproduction
In cattle, trophoblast cells in interplacentomal, arcade, and villous/crypt regions possess unique MHC-I ex
Normally, cattle have a greater number of lymphocytes in the non-gravid uterine horn than in the gravid horn. In early pregnancy, the endometrial lymphocytes decrease in number in sheep, pigs, and cattle. In 34-63 day old SCNT pregnancies, trophoblast MHC-I ex
These findings suggest that abnormal trophoblast MHC-I ex