The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

Abstract

Major histocompatibility complex E (MHC-E) is a highly conserved non-classical MHC-Ib molecule that predominantly binds and presents MHC-Ia leader sequence-derived peptides for natural killer cell regulation. However, MHC-E also binds pathogen-derived peptide antigens for presentation to CD8+ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. Here, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently up-regulated by viral pathogens, and bound and presented identical peptides to CD8+ T cells. Indeed, SIV-specific, Mamu-E-restricted CD8+ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4+ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.

Comparative genetics of the major histocompatibility complex in humans and nonhuman primates

“…An identical organization can be found for these genes in great apes. In OWM and NWM species, the organization of the genes seems to be similar; however, species‐specific expansion–contraction of the genes can be observed (Kono et al., 2014;Wu et al., 2018)…”

“…For NHP, MHC‐E polymorphism is most thoroughly investigated in the rhesus and cynomolgus macaque, and 33 and 16 different alleles are described encoding 30 and 14 proteins, respectively (Table 1). Rhesus and cynomolgus macaques may express 1–4 and 1–3 distinct MHC‐E transcripts, respectively, suggesting that the MHC‐E gene is duplicated in these species (Wu et al., 2018). Although the implications of this duplication in macaques are unclear, the HLA‐E and the macaque counterparts show conservation concerning their T‐cell immunity, which includes similar upregulation by viral pathogens and the presentation of identical viral peptides to CD8 + T cells (Wu et al., 2018).…”

HLA-E: exploiting pathogen-host interactions for vaccine development

“…Primate MHC is more polymorphic than human MHC, and Mamu-E itself exhibits further polymorphism than human HLA-E, with at least 33 functional alleles identified in rhesus macaque populations [24,26]. HLA-E and Mamu-E share 88% amino acid identity, especially within the peptide binding region of the protein [27], and there is conservation in function between rhesus macaques, cynomolgus macaques (M. fascicularis) and humans [26,27]. HLA-E and Mamu-E share 88% amino acid identity, especially within the peptide binding region of the protein [27], and there is conservation in function between rhesus macaques, cynomolgus macaques (M. fascicularis) and humans [26,27].…”

“…In mice and rats, the corresponding HLA-E orthologues are Qa-1b and RT-BM1, respectively [25], and Mamu-E is the HLA-E homologue in the rhesus macaque (Macaca mulatta) [24]. Primate MHC is more polymorphic than human MHC, and Mamu-E itself exhibits further polymorphism than human HLA-E, with at least 33 functional alleles identified in rhesus macaque populations [24,26]. However, Mamu-E is still the most conserved of all the class I MHC loci in macaques.…”

“…However, Mamu-E is still the most conserved of all the class I MHC loci in macaques. HLA-E and Mamu-E share 88% amino acid identity, especially within the peptide binding region of the protein [27], and there is conservation in function between rhesus macaques, cynomolgus macaques (M. fascicularis) and humans [26,27]. Mamu-E is also able to bind a wider range of peptides than HLA-E, although it still preferentially binds the canonical VL9 peptide [5].…”