HLA-G mRNA, protein isoforms, and receptors. (A) This HLA-G primary transcript is homologous to that of classic HLA class I molecules but contains a stop codon in exon 6, shortly after the coding sequence for the transmembrane domain. (B) Alternative splicing of the primary transcript yields 7 protein isoforms: truncated isoforms are generated by excision of one or 2 exons encoding globular domains, whereas translation of intron 4 or intron 2 yields soluble isoforms that lack the transmembrane domain. (C) HLA-G is well known to act through binding of inhibitory receptors, such as immunoglobulin-like transcript 2 (ILT2), ILT4, and killer-cell immunoglobulin-like receptor, 2 domains, long cytoplasmic tail, 4 (KIR2DL4), that are differentially expressed by immune cells, but binding to CD8 has also been reported.⁸⁸