Expression and genomic analyses of Camelus dromedarius T cell receptor delta (TRD) genes reveal a variable domain repertoire enlargement due to CDR3 diversification and somatic mutation

Antonacci, Rachele; Mineccia, Micaela; Lefranc, Marie‐Paule; Ashmaoui, Hassan M. El; Lanave, Cecilia; Piccinni, Barbara; Pesole, Graziano; Hassanane, M. S.; Massari, Serafina; Ciccarese, Salvatrice

doi:10.1016/j.molimm.2011.03.011

Cited by 23 publications

(36 citation statements)

References 44 publications

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“…In line with recent reports [13,14], the present study provides direct evidence that SHM heavily contributes to the expansion of the TCR γδ repertoire. This mechanism has long been considered typical of vertebrate immunoglobulins, occurring rarely in TCR [36,37].…”

Section: D) the Number Of The Mutations Occurring In (A/g/t)g(c/t)(a/supporting

confidence: 92%

“…Recently, it has been reported that SHM occurs also in the TCRGV region of the sandbar shark . In our opinion, our findings support the important conclusion that, as for TCRDV genes , the C. dromedarius TCRG gene repertoire is also likely to have been shaped by SHM. This latter result might have functional implications in terms of the role of γδ T cells in dromedary and for our understanding of the evolution of diversity‐generating mechanisms in the immune system of vertebrates.…”

Section: Introductionsupporting

confidence: 88%

“…5. Thus, these data demonstrate that somatic mutation occurs in both the dromedary TCRGV and TCRDV region [14], as well as in the sandbar shark TCRGV [13]. The TCR γ chain mutations do not show any bias for transition/transversion changes (Supporting Information Table 2A and B).…”

Section: Junctional Diversity and Somatic Mutations In Tcr γ Chainsmentioning

confidence: 62%

“…The rare occurrence of changes in C region sequences, the absence of changes in nine of the V domain sequences, and the presence of the same mutation in different clones confirms the high fidelity of the polymerase used. The changes observed consisted of 213 nucleotides substitutions, with an overall frequency of 0.008 per base pair (Table ), much higher than that of a nonrelevant gene (EEF1A1) . The average mutation rate does not depend on the number of PCR cycles, given that 19 of 22 TCRGV1‐TCRGJ1‐1 cDNA clones were obtained by half the number of PCR cycles with respect to the TCRGV2‐TCRGJ2‐2 clones.…”

Section: Resultsmentioning

confidence: 95%

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Generation of diversity by somatic mutation in theCamelus dromedariusT‐cell receptor gamma variable domains

et al. 2012

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In jawed vertebrates the V-(D)-J rearrangement is the main mechanism generating limitless variations of antigen-specific receptors, immunoglobulins (IGs), and T-cell receptors (TCRs) from few genes. Once the initial diversity is established in primary lymphoid organs, further diversification occurs in IGs by somatic hypermutation, a mechanism from which rearranged TCR genes were thought to be excluded. Here, we report the locus organization and expression of the T-cell receptor gamma (TCRG) genes in the Arabian camel (Camelus dromedarius). Expression data provide evidence that dromedary utilizes only two TCRG V-J genomic arrangements and, as expected, CDR3 contributes the major variability in the V domain. The data also suggest that diversity might be generated by mutation in the productively rearranged TCRGV genes. As for IG genes, the mutational target is biased toward G and C bases and (A/G/T)G(C/T)(A/T) motif (or DGYW). The replacement and synonymous substitutions (R/S) ratios in TCRGV regions are higher for CDR than for framework region, thus suggesting selection toward amino acid changes in CDR. Using the counterpart human TCR γδ receptor as a template, structural models computed adopting a comparative procedure show that nonconservative mutations contribute to diversity in CDR2 and at the γδ V domain interface. Keywords: Camelus dromedarius · Protein modeling · Somatic hypermutation · T-cell receptor gamma (TCRG) Supporting Information available onlineCorrespondence: Dr. Salvatrice Ciccarese e-mail: ciccarese@biologia.uniba.it IntroductionTo respond to the wide spectrum of antigenic determinants presented by an almost limitless variety of diverse and evolving pathogens, the metazoan immune system developed a striking C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 3416-3428 Molecular immunology 3417 variation of immune receptor molecules and diversification mechanisms [1]. In jawed vertebrates, the T-cell response is mediated by signaling from the T-cell receptors αβ and γδ, both encoded by complex multigene families. Genetic information for receptor chains is carried by a germline pool of variable (V), joining (J), and diversity (D) genes that undergo somatic DNA rearrangements to generate receptors with diverse-binding specificity [2]. The "innate-like" γδ T cells have unique features when compared with the more abundant αβ T cells, e.g. a preferential distribution in both epithelial and mucosal sites, an immunoglobulin (IG)-like antigen recognition mechanism in addition to the MHC-restricted one. Moreover, their percentage in peripheral blood cells, depending on age and species, differs strikingly from that of αβ T cells [3]. Artiodactyls are referred to as "γδ-high species" since they exhibit a higher frequency and a wider physiological distribution of γδ T cells with respect to other mammalian species, including humans and mice which are referred to as "γδ-low species" [4]. The locus organization and expression of TCRG and TCRD genes have been charac...

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Section: D) the Number Of The Mutations Occurring In (A/g/t)g(c/t)(a/supporting

confidence: 92%

Section: Introductionsupporting

confidence: 88%

Section: Junctional Diversity and Somatic Mutations In Tcr γ Chainsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 95%

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Generation of diversity by somatic mutation in theCamelus dromedariusT‐cell receptor gamma variable domains

et al. 2012

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“…Vaccarelli et al (2012) detected, at the T-cell receptor (TCR) gamma genes, SNPs with a frequency of one every 114 to 485 nucleotides, depending on the considered rearrangements, and somatic hypermutation was suggested on that locus as a mechanism to diversify the Camelus dromedarius TCR gene repertoire face to the wide spectrum of antigenic determinants presented by a variety of diverse and evolving pathogens. High nucleotide sequence diversity as a consequence of somatic hypermutation had been previously reported also for the T-cell receptor delta chains (Antonacci et al, 2011). We did not observe any polymorphism in the second exon of the myostatin, which is known from other species to harbor functional mutations (Baron et al, 2012).…”

Section: Resultssupporting

confidence: 71%

Sequence and polymorphism analysis of the camel (Camelus dromedarius) myostatin gene

Muzzachi

Oulmouden

Cherifi

et al. 2015

Emir. J. Food Agric

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Myostatin (MSTN), a negative regulator of skeletal muscle development in mammals, represents a key target for genetic investigations in meat-producing animals, with mutations responsible for increased skeletal-muscle mass currently described in several livestock species. Dromedary camels play a major economic role as suppliers of meat for human consumption across several countries. Notwithstanding, a comprehensive characterization of the sequence variability at the Camelus dromedarius MSTN locus was still lacking. Here we present the first extensive sequence and polymorphism analysis of the MSTN gene in the C. dromedarius species. Out of more than 3.6 kb of nucleotide sequence screened on 22 animals from 3 different Northern African regions, only 3 variant sites in the first intron were detected. The low observed diversity may reflect the evolutionary history of the species, likely developed as domesticates from a low variable wild ancestor population. Sequence identity among C. dromedarius and other Cetartiodactyla highlighted a tree topology consistent with previous reports of a closer relationship between Tylopoda and Suiformes. A close similarity between C. ferus and C. dromedarius was observed within Tylopoda. A markedly higher sequence identity between C. dromedarius and the other vertebrate species was observed at the MSTN locus compared to other genes, thus confirming it as a highly conserved target across mammals.

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Nurse shark T‐cell receptors employ somatic hypermutation preferentially to alter alpha/delta variable segments associated with alpha constant region

et al. 2020

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In addition to canonical TCR and BCR, cartilaginous fish assemble noncanonical TCR that employ various B‐cell components. For example, shark T cells associate alpha (TCR‐α) or delta (TCR‐δ) constant (C) regions with Ig heavy chain (H) variable (V) segments or TCR‐associated Ig‐like V (TAILV) segments to form chimeric IgV‐TCR, and combine TCRδC with both Ig‐like and TCR‐like V segments to form the doubly rearranging NAR‐TCR. Activation‐induced (cytidine) deaminase‐catalyzed somatic hypermutation (SHM), typically used for B‐cell affinity maturation, also is used by TCR‐α during selection in the shark thymus presumably to salvage failing receptors. Here, we found that the use of SHM by nurse shark TCR varies depending on the particular V segment or C region used. First, SHM significantly alters alpha/delta V (TCRαδV) segments using TCR αC but not δC. Second, mutation to IgHV segments associated with TCR δC was reduced compared to mutation to TCR αδV associated with TCR αC. Mutation was present but limited in V segments of all other TCR chains including NAR‐TCR. Unexpectedly, we found preferential rearrangement of the noncanonical IgHV‐TCRδC over canonical TCR αδV‐TCRδC receptors. The differential use of SHM may reveal how activation‐induced (cytidine) deaminase targets V regions.

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Expression and genomic analyses of Camelus dromedarius T cell receptor delta (TRD) genes reveal a variable domain repertoire enlargement due to CDR3 diversification and somatic mutation

Cited by 23 publications

References 44 publications

Generation of diversity by somatic mutation in theCamelus dromedariusT‐cell receptor gamma variable domains

Generation of diversity by somatic mutation in theCamelus dromedariusT‐cell receptor gamma variable domains

Sequence and polymorphism analysis of the camel (Camelus dromedarius) myostatin gene

Nurse shark T‐cell receptors employ somatic hypermutation preferentially to alter alpha/delta variable segments associated with alpha constant region

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