Do Nonhuman Primates Comprise Appropriate Experimental Models for Studying the Function of Human Leukocyte Antigen-G?1

Abstract

The expression and function of the human major histocompatibility complex (MHC) class Ia genes, human leukocyte antigen (HLA)-A, -B, and -C, is well-established; they are expressed in most nucleated cells and present endogenous peptides to CD8+ T cells. However, MHC class Ib genes are poorly characterized and have unknown functions. In humans, the best-characterized class Ib gene is HLA-G. This gene has a restricted tissue expression of the mRNA and a unique pattern of protein expression; it is expressed mainly in the extravillous cytotrophoblast cells in the placenta. The function of HLA-G is not clear, but its presence at the maternal-fetal interface suggests a role in protection of the semiallogeneic fetus. Whereas functional studies using in vitro models and transgenic mice provide useful insights regarding the potential function of this molecule, in vivo studies cannot be performed in humans. Nonhuman primates that are closely related to humans phylogenetically contain homologues of HLA-G. The MHC-G loci in nonhuman primates appear to have diverged from the human HLA-G. However, in the rhesus monkey (Macaca mulatta) and olive baboon (Papio anubis), a novel class Ia-related locus has been described. This gene encodes glycoproteins with characteristics that resemble those of HLA-G, including restricted tissue distribution, alternative splicing of mRNA, truncated cytoplasmic domain, and limited polymorphism. Thus, this molecule may be the functional homologue of HLA-G, and these two species may comprise appropriate models for elucidating the function of HLA-G.

The role of HLA-G in human pregnancy

“…[44,45]). In Old World monkeys that have been examined so far, the orthologue of HLA-G appears to be a pseudogene [46].…”

“…Despite the similarity to the HLA-A locus, the messages and proteins encoded by this gene are strikingly similar to those of the HLA-G locus (reviewed in Ref. [45,50]), leading to the hypothesis that the AG locus may be the functional homologue of HLA-G in these species.…”

Evolution of Killer Cell Ig-Like Receptor (KIR) Genes: Definition of an Orangutan KIR Haplotype Reveals Expansion of Lineage III KIR Associated with the Emergence of MHC-C

“…Of potential importance is that orangutan and rhesus 2DL4 have two ITIM motifs, whereas human and chimpanzee 2DL4 have only one. Further evidence for functional differences between these species is that rhesus MHC-G is unexpressed, possibly supplanted by the related MHC-AG (64,65), and that secreted HLA-G isoforms appear specific to the human species (66) and able to stimulate NK cells through endocytosis and signaling from intracellular vesicles (67). Thus, while KIR2DL4 is the most conserved KIR gene in the higher primates, its alleles and functions are continuing to evolve.…”

ORIGINAL ARTICLE: Suppression of Mamu‐AG by RNA Interference

“…Nonclassical MHC class I molecules are thought to contribute to the ability of the placenta to evade maternal attack. Mamu-AG is a nonclassical MHC class I molecule expressed in the rhesus monkey placenta thought to be the functional homolog of Human Leukocyte Antigen (HLA)-G in humans 1,2. Similarities include limited polymorphism, restricted tissue distribution, alternative splicing of mRNAs, a truncated cytoplasmic domain, a premature stop codon, and synthesis of multiple isoforms in trophoblasts 1,2.…”

“…Mamu-AG is a nonclassical MHC class I molecule expressed in the rhesus monkey placenta thought to be the functional homolog of Human Leukocyte Antigen (HLA)-G in humans 1,2. Similarities include limited polymorphism, restricted tissue distribution, alternative splicing of mRNAs, a truncated cytoplasmic domain, a premature stop codon, and synthesis of multiple isoforms in trophoblasts 1,2. Comparable to HLA-G, Mamu-AG is expressed at high levels in the placenta and has restricted low level expression in other tissues 3…”