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. 2024 Nov 13:15:1501934.
doi: 10.3389/fimmu.2024.1501934. eCollection 2024.

Extraordinary diversity of the CD28/CTLA4 family across jawed vertebrates

Sylvie M A Quiniou #  1 , Thomas Clark  2 , Eva Bengtén  3   4 , Jonathan P Rast  5 , Yuko Ohta  6 , Martin Flajnik  6 , Pierre Boudinot #  7
Affiliations

Extraordinary diversity of the CD28/CTLA4 family across jawed vertebrates

Sylvie M A Quiniou et al. Front Immunol. .

Abstract

Members of the CD28 family are critical for the control of immune cell activation. While CD28 and CTLA4 were previously identified in teleost fish, most members of the CD28 family have been described only in tetrapods. Using a comparative genomics approach, we found (co)orthologs of all members of the CD28 family both in Chondrichthyes and basal Osteichthyes groups, but not in Agnathans. Four additional members of the family were identified, which were present in both Chondrichthyes and Osteichthyes, some even in the tetrapod lineage but all of them absent in human. Herein, we extend the composition of the jawed vertebrate CD28 family to nine members: CD28, CTLA4, ICOS, CD28H, CD28HL1, CD28HL2, CD28HL3, CD28X and PD-1. Each of these genes had a single extracellular IgSF V domain, and conserved motifs in the V and the cytoplasmic domain. While a genomic cluster of three consecutive genes like CD28/CTLA4/ICOS was conserved across jawed vertebrates except in teleosts, the other members of the CD28 family were located on multiple chromosomes. Our findings show that these co-stimulatory/co-inhibitory receptors likely arose in early jawed vertebrates, and diversified when the Ig/TCR/MHC-based adaptive immunity emerged, heralding the advent of complex regulatory networks controlling lymphocyte activation.

Keywords: CD28; CD28H; CTLA4; ICOS; Immune checkpoints; PD1; costimulatory receptors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Schematic phylogenetic tree of the taxonomic groups considered in this study. Taxonomy as in Helfman et al. (2010) for fish and in NCBI. (B) Domains and motifs generally conserved in members of the CD28 family. The GxG motif present in CTLA4 G-strand is not present in all members and is indicated with “()”. (C) Evolutionary analysis of CD28, CTLA4, ICOS and chondrichthyan CD8/CTLA4 homologs. The evolutionary history was inferred by using the Maximum Likelihood method and JTT matrix-based model. The tree with the highest log likelihood (-15105.34) is shown. The percentage of trees in which the associated taxa clustered together is shown next to the branches. Initial tree(s) for the heuristic search were obtained by applying the BioNJ method to a matrix of pairwise distances estimated using a JTT model. A discrete Gamma distribution was used to model evolutionary rate differences among sites. The number at the end of chondrichthyan genes refers to their position in the genomic cassette of three CD28/CTLA4 genes.
Figure 2
Figure 2
Conserved synteny blocks with CD28 (striped blue and white), CTLA4 (yellow), ICOS (pink) and chondrichthyan CD28/CTLA4 homologs (orange). Consecutive gene groups are boxed in grey. Only conserved markers are represented in the regions of interest, of which start and end location are indicated in the reference NCBI chromosome/LG of each species.
Figure 3
Figure 3
The repertoire of CD28 family members. (A) Multiple alignment of the CD28 family member AA sequences of the species with the widest repertoire, the spotted gar. A PD-1 putative homolog was identified in the spotted gar but the protein model lacked key motifs and might be partial, hence the sterlet sequence was included in the figure for a better representativity. Similarity matrix (B) and unrooted ML phylogenetic tree (C) of Spotted gar sequences showing clustering of CD28H with CD28HL sequences.
Figure 4
Figure 4
Conserved synteny blocks with CD28H (dark grey). Only conserved markers are represented in the regions of interest, of which start and end location are indicated in the reference NCBI chromosome/LG of each species.
Figure 5
Figure 5
Evolutionary analysis of CD28, CD28H and CD28X (A) or CD28H and CD28HL1-3 (B). As in Figure 1C , the evolutionary history was inferred by using the Maximum Likelihood method and JTT matrix-based model. The trees with the highest log likelihood are shown, and the percentage of trees in which the associated taxa clustered together is shown next to the branches.
Figure 6
Figure 6
Conserved synteny blocks with PD-1 (white P on black background). Only conserved markers are represented in the regions of interest, and start and end locations are indicated in the reference NCBI chromosome/LG of each species. PD-1 genes encoding a divergent IgV domain are indicated with a “?”.
Figure 7
Figure 7
Evolution of the repertoire of CD28 family members in vertebrates. The “?” and “()” refer to the PD-1 homolog with degenerated IgV domain in bony fish species. The red stars denote whole genome duplication events.
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