Full-length HLA-G1 and truncated HLA-G3 differentially increase HLA-E surface localization.

Human leukocyte antigen (HLA)-E and -G belong to the non-classical major histocompatibility (MHC) class Ib family, widely recognized for its limited polymorphism. Although HLA-E mRNA has been widely detected in postnatal tissues, its surface expression is restricted due to the requirement that specific short peptides bind its α-chain to facilitate endoplasmic reticulum (ER) egress. Examples of such peptides include nonamers derived from N-terminal leader sequences of HLA class I proteins, all of which possess different binding affinities for HLA-E and variable effects on HLA-E surface localization. Evidence to date suggests HLA-A2 and HLA-B7 signal peptides possess the highest affinity for HLA-E with the greatest enhancement of surface expression. Recent studies found the peptide present in the leader sequences of the human cytomegalovirus glycoprotein UL40 could also enhance HLA-E surface expression. Although the direct tolerogenic role of HLA-G has been well established, its indirect tolerogenic effects through HLA-E remain unclear. One study demonstrated that the truncated and soluble isoforms of HLA-G are less efficient in providing HLA-E ligand to enhance ER egress. However, others believe that the truncated isoform, HLA-G3, is sufficient to upregulate HLA-E surface expression despite not reaching the cell surface itself. Thus, the effects of full-length versus truncated isoforms of HLA-G on HLA-E surface localization remain unclear. In this study, we clarify this question by assessing HLA-E surface expression in human cells heterologously expressing HLA-G1 and -G3. Our study revealed that HLA-E surface localization could be upregulated by not only full-length but also truncated HLA-G although the latter resulted in less efficient HLA-E translocation. This suggests that full-length and truncated isoforms may serve unique functional roles in immune regulation, and further underscores the importance of conducting additional studies aimed at clarifying the mechanisms underlying this differential regulation.