T cell receptor CDR3 loop length repertoire is determined primarily by features of the V(D)J recombination reaction.
ABSTRACT The third complementarity-determining region (CDR) of the TCR alpha and beta chains forms loops that engage amino acid residues of peptides complexed with MHC. This interaction is central to the specific discrimination of antigenic-peptide-MHC complexes by the TCR. The TCRbeta chain CDR3 loop is encoded by the Dbeta gene segment and flanking portions of the Vbeta and Jbeta gene segments. The joining of these gene segments is imprecise, leading to significant variability in the TCRbeta chain CDR3 loop length and amino acid composition. In marked contrast to other pairing antigen-receptor chains, the TCR beta and alpha chain CDR3 loop size distributions are relatively narrow and closely matched. Thus, pairing of TCR alpha and beta chains with relatively similar CDR3 loop sizes may be important for generating a functional repertoire of alpha beta TCR. Here we show that the TCRbeta chain CDR3 loop size distribution is minimally impacted by TCRbeta chain or alpha beta TCR selection during thymocyte development. Rather, this distribution is determined primarily at the level of variable-region gene assembly, and is critically dependent on unique features of the V(D)J recombination reaction that ensure Dbeta gene segment utilization.
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ABSTRACT: TCRbeta chain repertoire of peripheral alphabeta T cells is generated through the stepwise assembly and subsequent selection of TCRbeta V region exons during thymocyte development. To evaluate the influence of a two-step recombination process on Vbeta rearrangement and selection, we generated mice with a preassembled Dbeta1Jbeta1.1 complex on the Jbeta1(omega) allele, an endogenous TCRbeta allele that lacks the Dbeta2-Jbeta2 cluster, creating the Jbeta1(DJbeta) allele. As compared with Jbeta1(omega/omega) mice, both Jbeta1(DJbeta/omega) and Jbeta1(DJbeta/DJbeta) mice exhibited grossly normal thymocyte development and TCRbeta allelic exclusion. In addition, Vbeta rearrangements on Jbeta1(DJbeta) and Jbeta1(omega) alleles were similarly regulated by TCRbeta-mediated feedback regulation. However, in-frame VbetaDJbeta rearrangements were present at a higher level on the Jbeta1(DJbeta) alleles of Jbeta1(DJbeta/omega) alphabeta T cell hybridomas, as compared with on the Jbeta1(omega) alleles. This bias was most likely due to both an increased frequency of Vbeta-to-DJbeta rearrangements on Jbeta1(DJbeta) alleles and a preferential selection of cells with in-frame VbetaDJbeta exons assembled on Jbeta1(DJbeta) alleles during the development of Jbeta1(DJbeta/omega) alphabeta T cells. Consistent with the differential selection of in-frame VbetaDJbeta rearrangements on Jbeta1(DJbeta) alleles, the Vbeta repertoire of alphabeta T cells was significantly altered during alphabeta TCR selection in Jbeta1(DJbeta/omega) and Jbeta1(DJbeta/DJbeta) mice, as compared with in Jbeta1(omega/omega) mice. Our data indicate that the diversity of DJbeta complexes assembled during thymocyte development influences TCRbeta chain selection and peripheral Vbeta repertoire.The Journal of Immunology 06/2009; 182(9):5586-95. · 5.52 Impact Factor
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ABSTRACT: V(D)J recombination assembles antigen receptor genes from germline V, D and J segments during lymphocyte development. In αβT-cells, this leads to the subsequent expression of T-cell receptor (TCR) β and α chains. Generally, V(D)J recombination is closely controlled at various levels, including cell-type and cell-stage specificities, order of locus/gene segment recombination, and allele usage to mediate allelic exclusion. Many of these controls rely on the modulation of gene accessibility to the recombination machinery, involving not only biochemical changes in chromatin arrangement and structural modifications of chromosomal organization and positioning, but also the refined composition of the recombinase targets, the so-called recombination signal sequences. Here, we summarize current knowledge regarding the regulation of V(D)J recombination at the Tcrb gene locus, certainly one for which these various levels of control and regulatory components have been most extensively investigated.Seminars in Immunology 12/2010; 22(6):330-6. · 5.93 Impact Factor
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ABSTRACT: Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.Cell Research 01/2012; 22(1):33-42. · 10.53 Impact Factor