B7-H6/NKp30 interaction: a mechanism of alerting NK cells against tumors

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune system that sense target cells through a panel of activating and inhibitory receptors. Together with NKG2D, the natural cytotoxicity receptors (NCRs) are major activating receptors involved in tumor cell detection. Although numerous NKG2D ligands have been identified, characterization of the molecules interacting with the NCRs is still incomplete. The identification of B7-H6 as a counter structure of the NCR NKp30 shed light on the molecular basis of NK cell immunosurveillance. We review here the current knowledge on NKp30 and B7-H6, and we discuss their potential role in anti-tumor immunity.

Fig. 1

Phylogenic analysis of NKp30 protein sequences in mammals. The tree was constructed from CLUSTALW-generated amino acid alignments using the neighbor-joining method. Tree topography was evaluated by bootstrapping 1,000 times with percentage shown at nodes. Each node shows the percentage of the bootstrap replicates in which all of the sequences descended from that node were also descended from that node in the replicates. The tree is drawn to scale with branch lengths in the same units as those of the evolutionary distances used to infer phylogenetic tree. Phylogenetic analyses were conducted in Seaview. Primates are included in the shaded area

Fig. 2

Gene organization of B7-H6 and NKp30 in comparison to the other members of the B7 and CD28 family. Each box represents an exon encoding the indicated domain (leader in grey, IgV in blue, IgC in red, transmembrane in dark grey, GAG domain in green, untranslated region in white, and others in black). Numbers between boxes indicate the intron phase. Canonical sequences of each gene were used to design these schemes (www.uniprot.org)

Fig. 3

Comparison of the CTLA-4 homodimer crystallographic structure and the structure of the NKp30 homodimer obtained by homology modeling. a NKp30 homodimer model and b CTLA-4 homodimer crystallographic structure (3OSK). Both structures are shown in ribbon representation, respectively, β-strands colored in red, coil in cyan, and β-turns in green. Amino acid residues found important for CTLA-4 B7.1/B7.2 interaction, for N-glycosylation, and for dimer stabilization as well as their NKp30 modeled equivalents are represented as sticks colored according to elements and residues are one letter named and numbered. Cysteines are represented as sticks with yellow color. N- and C-termini of both proteins are labeled. c Superposition of NKp30 (red) and CTLA-4 (green) monomers

Fig. 4

The human NKp30 gene encodes six splice variants. The genomic organization of the exons contributing to the six transcript variants (NKp30a–f) is represented in the top panel. In transcripts a, b, and c the exon 2 is used, whereas in transcripts d, e, and f, both exon 2I and 2II are used, resulting in a 75-nt deletion. The initiation and stop codons are indicated by the arrowheads. The bottom panel represents the protein structure of each variant. NKp30a–c have an IgV domain, whereas NKp30d–f have an IgC domain

Fig. 5

The B7 family mirrors the diversity of the CD28 members. Evolutionary relationships of human B7 (blue) and CD28 (black) family members were inferred using the neighbor-joining method. Tree topography was evaluated by bootstrapping 1,000 times with percentage shown at nodes (see legend of Fig. 1 for details). Arrows indicate the interacting receptors and ligands

Fig. 6

Phylogenic analysis of the B7-H6 protein sequences in mammals. Left part: the tree was constructed from CLUSTALW generated amino acid alignments using the neighbor-joining method. Tree topography was evaluated by bootstrapping 1,000 times with percentage shown at nodes (see legend of Fig. 1 for details). Phylogenetic analyses were conducted in Seaview. Primates are included in the shaded area. Right part: schematic representation of the predicted protein for each species. Percentage of similarity with the human B7-H6 protein is indicated for each domain (white leader or interdomain, blue IgV domain, red IgC domain, green GAG domain)