Structural Comparison Between MHC Classes I and II; in Evolution, a Class-II-Like Molecule Probably Came First

Abstract

Structures of peptide-loaded major histocompatibility complex class I (pMHC-I) and class II (pMHC-II) complexes are similar. However, whereas pMHC-II complexes include similar-sized IIα and IIβ chains, pMHC-I complexes include a heavy chain (HC) and a single domain molecule β2-microglobulin (β2-m). Recently, we elucidated several pMHC-I and pMHC-II structures of primitive vertebrate species. In the present study, a comprehensive comparison of pMHC-I and pMHC-II structures helps to understand pMHC structural evolution and supports the earlier proposed—though debated—direction of MHC evolution from class II-type to class I. Extant pMHC-II structures share major functional characteristics with a deduced MHC-II-type homodimer ancestor. Evolutionary establishment of pMHC-I presumably involved important new functions such as (i) increased peptide selectivity by binding the peptides in a closed groove (ii), structural amplification of peptide ligand sequence differences by binding in a non-relaxed fashion, and (iii) increased peptide selectivity by syngeneic heterotrimer complex formation between peptide, HC, and β2-m. These new functions were associated with structures that since their establishment in early pMHC-I have been very well conserved, including a shifted and reorganized P1 pocket (aka A pocket), and insertion of a β2-m hydrophobic knob into the peptide binding domain β-sheet floor. A comparison between divergent species indicates better sequence conservation of peptide binding domains among MHC-I than among MHC-II, agreeing with more demanding interactions within pMHC-I complexes. In lungfishes, genes encoding fusions of all MHC-IIα and MHC-IIβ extracellular domains were identified, and although these lungfish genes presumably derived from classical MHC-II, they provide an alternative mechanistic hypothesis for how evolution from class II-type to class I may have occurred.

Some thoughts about what non-mammalian jawed vertebrates are telling us about antigen processing and peptide loading of MHC molecules

“…For the surviving members of the jawless fish lampreys and hagfish (the earliest fish group to appear in the evolutionary record), there is an adaptive immune system with three kinds of antigen-specific receptors based on leucine-rich repeats, but no genes with obvious similarity to or properties like MHC genes have been reported 23 , 24 . However, the discovery of the so-called W genes in sharks, various bony fish and salamanders shows that class II genes preceded the appearance of class I genes [25••] , finally laying to rest the controversy over which came first [26•] . The W genes are present in AB gene pairs and are expressed as αβ heterodimers with the domain structure of class II molecules, but have many key sequence features of class I molecules.…”

PANDORA: A Fast, Anchor-Restrained Modelling Protocol for Peptide: MHC Complexes

“…Each of these alleles has a specific binding preference for different peptides. Regardless of the highly polymorphic nature of MHC sequence, the MHC structure has an “Ultra-conserved” fold ( 17 ), which is present in nearly all jawed vertebrate species ( 12 , 14 ). In MHC-I molecules, the peptide binding groove is formed by an α -chain, which has two domains denoted as G-ALPHA1 and G-ALPHA2 in IMGT nomenclature ( 18 ) ( Figure 1A ).…”

Anti-Inflammatory and Pro-Autophagy Effects of the Cannabinoid Receptor CB2R: Possibility of Modulation in Type 1 Diabetes

“…Human CB1R (472 AA) is enriched in neurons and is more homologous to chordate ciCBR and bfCBR ( Elphick, 2007 ). CB2R (360 AA) is enriched in the immune system ( Liu et al, 2020a ) and CNR2 likely arose due to vertebrate genome duplication about 500 million years ago ( Elphick, 2002 ) when the adaptive immune system and major histocompatibility complex class I (MHC-I) and class II (MHC-II) are reported to have first appeared in jawed fish ( Flajnik and Kasahara, 2010 ; Wu et al, 2021 ). During mammalian evolution, human gene exonization ( Li et al, 2018 ) and splicing isoform evolution ( Zhang et al, 2017a ) contributed to multiple upstream exons with a single promoter in CNR1 and two promoters in CNR2 ( González-Mariscal et al, 2016 ; Liu et al, 2009 ) to diversify eCB signaling in a specific cell type context ( Marti-Solano et al, 2020 ) and the genomic size of CNR2 is more than 3-fold larger than that of CNR1 ( Figures 2A,B ).…”

“…Pancreatic β-cells do not express MHC-II because it is restricted to professional antigen presenting cells (APCs), such as CB2R enriched macrophages, dendritic and B cells ( Roche and Furuta, 2015 ). The β-cells secrete and present the autoantigens that are endocytosed by APCs and fused with lysosomes, and further processed by endosome-lysosome pathway ( Lundberg and McDevitt, 1992 ) to peptides of 12–25 AAs ( Wu et al, 2021 ) that bind to MHC-II-Ii (Invariant chain) complex in ER and translocate via Golgi apparatus to endolysosomes in which Ii is cleaved by cathepsin L and the remaining CLIP (class II-associated invariant chain peptide) prevents autoantigen presentation to APCs that regulate CD4 + T cell differentiation ( Jurewicz and Stern, 2019 ). During inflammation, the activated APCs present more β-cell-derived neo- and autoantigen peptides that stimulate pathological Th17 cytotoxic cell expansion in lymph nodes and in circulation ( Honkanen et al, 2010 ).…”