Structure, diversity, and evolution of the T-cell receptor VB gene repertoire in primates

Abstract

AB T-cell receptors (TCR) that recognize major histocompatibility complex (MHC)/peptide antigen complexes regulate humoral and cellular arms of the adaptive immune response. Antigen binding sites of MHC and immunoglobulin heavy chain variable regions (Igh-V) are subject to diversity enhancing selection. We sought to establish whether positive Darwinian selection has driven diversity of TCRBV chains in the primate lineage by sequencing rearranged TCR from rhesus monkeys and chimpanzees and comparing them with those of humans. Rates of synonymous (silent) and nonsynonymous (replacement) substitutions indicate selection against amino acid replacements in TCRBV frameworks, and relaxation of these constraints in putative MHC/peptide contact sites. The lack of positive selection for variability in likely ligand contact sites suggests that mechanisms generating somatic diversity in TCR junctional regions have relaxed the pressure for selection of variability in the TCR V region encoded in the germline.

Analysis of the TCR β Variable Gene Repertoire in Chimpanzees: Identification of Functional Homologs to Human Pseudogenes

“…A previous study evaluating TCR evolution between primate species found similar results for the comparison of TCR sequences between Rhesus macaques and humans, with lower rates of synonymous and nonsynonymous mutations in framework compared with CDR regions of the TCR (21). In that study, a similar analysis comparing chimpanzee to human TCR sequences did not find significant differences in mutation rates of framework and CDR regions between species.…”

“…In addition to the highly similar structure of the TCRBV repertoire between species (i.e., the same number and similar size of TCRBV families) there was also a high degree of similarity between the individual genes, with a substantial proportion of genes having identical amino acid sequences as described before for the BV4-1 (BV7S1) gene (21). This high degree of phylogenetic relationship has led to the conclusion that the TCR repertoire as observed in humans and chimpanzees might be highly optimized, leaving little room for extensive genetic variation (20 -22).…”

“…Previous work demonstrated a close phylogenetic relationship between some human and chimpanzee TCRAV (43) and TCRBV genes (20,21). However, for a substantial proportion of human TCRBV genes, no chimpanzee homologues have yet been described.…”

Functional and Structural Similarity of Vγ9Vδ2 T Cells in Humans and Aotus Monkeys, a Primate Infection Model for Plasmodium falciparum Malaria

“…Hence the interspecies diversity of TRGV9 sequences is smaller than the intraspecies differences of other TRGV gene segments (34). The observation that TCR chain gene segments of nonhuman primates cluster in phylogenetic analyses according to family membership instead of species designations has been also described for TCR ␣-and ␤-chain gene segments (35)(36)(37)(38)(39)(40). The high evolutionary conservation of TRGV9 sequences during more than 50 million years in conjunction with the conserved features of TCR rearrangements found in V␥9V␦2 T cells responding to IPP suggests that these cells represent an evolutionary conserved immune surveillance system.…”

Acute Hepatitis C

“…32 (HCV is hepatotropic and replicates efficiently in chimpanzees-and the genotype 1 strain, HCV-1, typically establishes chronic infection. Exceptionally for an animal model of human disease, chimpanzees share with humans orthologous MHC 51,52 and TCR 53,54 genes.) This study revealed that a multispecific, intrahepatic CD8 ϩ CTL response during early infection correlated with HCV-1 clearance.…”