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

Abstract

Chimpanzees are used for a variety of disease models such as hepatitis C virus (HCV) infection, where Ag-specific T cells are thought to be critical for resolution of infection. The variable segments of the TCR αβ genes are polymorphic and contain putative binding sites for MHC class I and II molecules. In this study, we performed a comprehensive analysis of genes that comprise the TCR β variable gene (TCRBV) repertoire of the common chimpanzee Pan troglodytes. We identified 42 P. troglodytes TCRBV sequences representative of 25 known human TCRBV families. BV5, BV6, and BV7 are multigene TCRBV families in humans and homologs of most family members were found in the chimpanzee TCRBV repertoire. Some of the chimpanzee TCRBV sequences were identical with their human counterparts at the amino acid level. Notably four successfully rearranged TCRBV sequences in the chimpanzees corresponded to human pseudogenes. One of these TCR sequences was used by a cell line directed against a viral CTL epitope in an HCV-infected animal indicating the functionality of this V region in the context of immune defense against pathogens. These data indicate that some TCRBV genes maintained in the chimpanzee have been lost in humans within a brief evolutionary time frame despite remarkable conservation of the chimpanzee and human TCRBV repertoires. Our results predict that the diversity of TCR clonotypes responding to pathogens like HCV will be very similar in both species and will facilitate a molecular dissection of the immune response in chimpanzee models of human diseases.

Fluctuations of functionally distinct CD8+ T-cell clonotypes demonstrate flexibility of the HIV-specific TCR repertoire

“…We determined the structure of the epitope-specific TCR repertoire by sequencing ex vivo-purified HIV-specific CD8 ϩ T cells and by staining with a panel of monoclonal antibodies specific for 24 V␤ regions as previously described. 1,4,6,40 A recent study reported preferential V␤ 13.2 gene usage by B8-FL8-specific CD8 ϩ T cells in subjects maintaining CD4 counts more than 500 for longer than 8 years. 46 Although we observed an overrepresentation of certain V␤ regions within the epitope-specific TCR repertoire, most of our subjects used structurally diverse TCRs with different V␤ regions and with high amino acid diversity within the antigen recognition site of TCR␤ chains.…”

“…1,4,6,40 In subjects AC-14 and AC-15, 6 and 7 different clonotypes, respectively, could be detected within the B8-FL8-specific CD8 ϩ TCR repertoire. Most CDR3 amino acid sequences were heterogenous, and there was no common motif detectable throughout the sequences.…”

Aberrant termination of reproduction-related TMEM30C transcripts in the hominoids

“…In addition to amino acid substitution, divergence at a transcriptional level, such as cis-regulated gene expression divergence and the gainand-loss of genes, is likely to be an important factor in the genomic evolution of organisms to create phenotypic complexity (King and Wilson, 1975;Enard et al, 2002a;Heissig et al, 2005;Marques et al, 2005;Rockman et al, 2005). Although gains-and-losses of genes might cause a larger phenotypic effect than single amino acid substitutions (Olson and Varki, 2003), fewer studies have described lineage-specific gains-and-losses of genes among higher primates (Chou et al, 1998;Stedman et al, 2004;Hahn and Lee, 2005;Hayakawa et al, 2005;Wang et al, 2006), with the exception of the frequent births and deaths of genes in large multi-copied gene families (Meyer Olson et al, 2003;Fortna et al, 2004;Gilad et al, 2005;Go et al, 2005). Using the human and chimpanzee genome sequence, we could conduct a genome-wide survey of species-specific pseudogenes, which carry null mutations in the coding region either in the human and chimpanzee (Hahn and Lee, 2005;Wang et al, 2006).…”

Antiretroviral Therapy Reduces the Magnitude and T Cell Receptor Repertoire Diversity of HIV-Specific T Cell Responses without Changing T Cell Clonotype Dominance

“…The diversity of the TCR CDR3 region was determined using the Shannon entropy index (H) (31,49) calculation for protein sites as described previously (53), using the formula H ϭ Ϫ⌺p i log 2 p i , where p i is the fraction of residues at a site that is amino acid type i. For amino acids in the CDR3 region, H can range from 0 (site contains only one amino acid in all sequences) to 4.32 (all amino acids are represented equally at this site).…”