![]() While a secreted sHLA-E transcript has not yet been documented, there is some support from the western blotting of endothelial cells 39. These sHLA molecules can result from surface shedding, cleavage by metalloproteinases, or secretion via alternative splicing 38. There is an increasing body of evidence linking soluble (s)HLA with downregulated T cell responses 34 and a variety of immune disorders 35, 36, 37. Mamu-AG, the RM ortholog, also shares this extensive alternative splicing 33. In contrast, HLA-G, a separate MHC Class Ib gene, has seven known transcript variants: four membrane-bound and three secreted in soluble form 32. 31, and three additional HLA-E transcript variants predicted using EST and mRNA support. The most recent RefSeq annotations for HLA-E and Mamu-E contain a single transcript with the canonical MHC Class I exon/intron splicing, originally described by Malissen et al. We also recently showed that an Interleukin-15 response signature in whole blood predicts RhCMV/SIV vaccine efficacy 30, but it is still not clear if Mamu-E genetic diversity might also contribute to differences in RhCMV/SIV protection outcome.Įvidence suggests MHC-E expression and function may be regulated by alternative splicing. ![]() Furthermore, Mamu-E intracellular transport is now known to be necessary for vaccine efficacy and is driven by the genetic architecture of RhCMV 29. It was later shown that this protection was driven by RM MHC-E (Mamu-E)-restricted peptide antigen recognition by CD8 + T cells 27, 28. ![]() In a recent rhesus RhCMV/SIV vaccine study, 55% of RMs were protected from a highly pathogenic strain of SIV 9, 10. Together, these unique characteristics make MHC-E a crucial target for ongoing CMV-based vaccine development 24, 25, 26. Furthermore, human leukocyte antigen (HLA)-E, the human MHC-E ortholog, possesses the ability to present both self- and pathogen-derived sequences 21, 22, and its surface expression can be induced by human cytomegalovirus (hCMV) 23. This unconventional role of MHC-E in T-cell immunity is conserved between humans and RMs 20. As a non-classical MHC molecule, MHC-E dually functions in innate and adaptive immunity by interacting with T cells in addition to NK cells 19. Intriguingly, the genetic architecture and polymorphisms of MHC class I and II genes differ significantly among primates 15, posing a challenge for translational interpretation of non-human primate models in general.Īmong primate MHC Class I genes, the MHC-E locus is long considered as the most conserved 16, 17 and is believed to exist without duplication in both RM and human 18. RMs also serve as vaccination models against SARS-CoV-2 11, Mycobacterium tuberculosis 12, 13, and influenza A virus 14. Rhesus macaques (RMs) have been an important nonhuman primate model for the study of many of these human diseases 8 and are critical for pre-clinical trial vaccine development for protection against human immunodeficiency virus (HIV) using SIV infection in RMs 9, 10. Assigned with the critical role of distinguishing self from non-self, MHC Class I and II genes contain genetic variations that have been associated with hundreds of autoimmune and infectious diseases in human 5, 6, 7. MHC is constitutively expressed in nearly all nucleated cells and harbors significant genomic complexity 1, 2, 3, 4. The major histocompatibility complex (MHC) plays an essential role in host immune regulation. These genomic resources will facilitate additional MHC-E targeted translational research. Among four groups of Mamu-E alleles: three ~5% divergent full-length allele groups (G1, G2, G2_LTR) and a fourth monomorphic group (G3) with a deletion encompassing the canonical Mamu-E exon 6, the presence of G2_LTR alleles was significantly (p = 0.02) associated with the lack of RhCMV/SIV vaccine protection. ![]() ![]() The Mamu-E gene was duplicated in 32 (54%) of 59 RM. We also obtained the complete Mamu-E genomic sequences covering the full coding regions of 59 RM from a RhCMV/SIV vaccine study. Using long-read sequencing, we identified 16 Mamu-E isoforms and all Mamu-E splicing junctions were detected among HLA-E isoforms in humans. However, it is unclear how accurately the RM model reflects HLA-E immunobiology in humans. Rhesus cytomegalovirus (RhCMV)-based vaccination against Simian Immunodeficiency virus (SIV) elicits MHC-E-restricted CD8+ T cells that stringently control SIV infection in ~55% of vaccinated rhesus macaques (RM). ![]()
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