Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC

Abstract

The B7 family of genes is essential in the regulation of the adaptive immune system. Most B7 family members contain both variable (V)- and constant (C)-type domains of the immunoglobulin superfamily (IgSF). Through in silico screening of the Xenopus genome and subsequent phylogenetic analysis, we found novel genes belonging to the B7 family, one of which is the recently discovered B7H6. Humans and rats have a single B7H6 gene, however many B7H6 genes were detected in a single large cluster in the Xenopus genome. The B7H6 expression patterns also varied in a species-specific manner. Human B7H6 binds to the activating natural killer receptor, NKp30. While the NKp30 gene is single-copy and maps to the MHC in most vertebrates, many Xenopus NKp30 genes were found in a cluster on a separate chromosome that does not harbor the MHC. Indeed, in all species so far analyzed from sharks to mammals, the number of NKp30 and B7H6 genes correlates well, suggestive of receptor-ligand co-evolution. Furthermore, we identified a Xenopus-specific B7 homolog (B7HXen) and revealed its close linkage to B2M, which we have demonstrated previously to have been originally encoded in the MHC. Thus, our study provides further proof that the B7 precursor was included in the proto MHC. Additionally, the comparative analysis revealed a new B7 family member, B7H7, which was previously designated in the literature as an unknown gene, HHLA2.

The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways

“…The best blast hits of most of these markers were clustered in one 9.7-Mb scaffold (scaffold 2) of T. adhaerens, which also contained homologs of typical MHC markers. We therefore undertook a systematic survey of T. adhaerens homologs of all 7957 human genes located within the 19 genomic regions corresponding to MHC-, neurotrophin-, and JN-paralogons (21,25,49,50). Sequences of the longest protein isoforms encoded by each of these genes were extracted from the human genome assembly and were used as query for reciprocal D-BLAST (51) searches against the predicted proteome of T. adhaerens.…”

“…Identification and analysis of T. adhaerens counterparts of human genes located in MHC-, neurotrophin-, and JN-related paralogons Human protein-coding genes located within the genomic regions described as MHC-, neurotrophin-, and JN paralogons in (21,49), and within the MHC-related region defined by the R4 RGS genes (50) were extracted from Ensembl Genome Browser release 70 (human genome assembly GRCh37; 7957 genes). The sequence of the longest protein isoform encoded by each gene was extracted using Ensembl Biomart.…”

“…1B for definitions) with some overlaps (e.g., B7 receptors were spread over those three regions) (21) and breaks. Ohno's hypothesis of two cycles of whole genome duplications in ancestral vertebrates is supported by the study of hox complexes, and it applies to the MHC-related complexes as well as other regions (22)(23)(24)(25)(26)(27)(28)(29)(30).…”

CD28 family of receptors inter-connect in the regulation of T-cells

“…The ligand for CD28H has been identified as HERV-H LTR-associating 2 (HHLA2) renamed B7H7 [37,39] . Similar to CD28H, B7H7 orthologues are not present in laboratory mice or rats [40] .…”

“…Similar to CD28H, B7H7 orthologues are not present in laboratory mice or rats [40] . B7H7 possesses an IgV-IgC-IgV domain in its extracellular region [39] , and is expressed in intestines, breast, kidney, gallbladder, placenta and B cells [37,40] . B7H7 is believed to interact with CD28H via its first IgV domain and to send a co-stimulatory signal [37] , or co-inhibitory signal in the presence or absence of CD28H expression [38,41] .…”