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TCR? repertoire of CD4+ and CD8+ T cells is distinct in richness, distribution, and CDR3 amino acid composition.

ABSTRACT: The TCR repertoire serves as a reservoir of TCRs for recognizing all potential pathogens. Two major types of T cells, CD4(+) and CD8(+), that use the same genetic elements and process to generate a functional TCR differ in their recognition of peptide bound to MHC class II and I, respectively. However, it is currently unclear to what extent the TCR repertoire of CD4(+) and CD8(+) T cells is different. Here, we report a comparative analysis of the TCR? repertoires of CD4(+) and CD8(+) T cells by use of a 5' rapid amplification of cDNA ends-PCR-sequencing method. We found that TCR? richness of CD4(+) T cells ranges from 1.2 to 9.8 × 10(4) and is approximately 5 times greater, on average, than that of CD8(+) T cells in each study subject. Furthermore, there was little overlap in TCR? sequences between CD4(+) (0.3%) and CD8(+) (1.3%) T cells. Further analysis showed that CD4(+) and CD8(+) T cells exhibited distinct preferences for certain amino acids in the CDR3, and this was confirmed further by a support vector machine classifier, suggesting that there are distinct and discernible differences between TCR? CDR3 in CD4(+) and CD8(+) T cells. Finally, we identified 5-12% of the unique TCR?s that share an identical CDR3 with different variable genes. Together, our findings reveal the distinct features of the TCR? repertoire between CD4(+) and CD8(+) T cells and could potentially be used to evaluate the competency of T cell immunity.

SUBMITTER: Li HM

PROVIDER: S-EPMC5338248 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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TCRβ repertoire of CD4+ and CD8+ T cells is distinct in richness, distribution, and CDR3 amino acid composition.

Li Hoi Ming HM Hiroi Toyoko T Zhang Yongqing Y Shi Alvin A Chen Guobing G De Supriyo S Metter E Jeffrey EJ Wood William H WH Sharov Alexei A Milner Joshua D JD Becker Kevin G KG Zhan Ming M Weng Nan-ping NP

Journal of leukocyte biology 20150922 3

The TCR repertoire serves as a reservoir of TCRs for recognizing all potential pathogens. Two major types of T cells, CD4(+) and CD8(+), that use the same genetic elements and process to generate a functional TCR differ in their recognition of peptide bound to MHC class II and I, respectively. However, it is currently unclear to what extent the TCR repertoire of CD4(+) and CD8(+) T cells is different. Here, we report a comparative analysis of the TCRβ repertoires of CD4(+) and CD8(+) T cells by ...[more]

PMID: 26394815

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Project description:The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCR?? sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCR? chain. For the first time, we identify a CDR3? (complementarity determining region 3 ?) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCR? chains within the same donor (median 4; range: 1-9), suggests that there are some unique structural features of the interaction between the YVL-BR/MHC and the AV8.1-KDTDKL-AJ34 TCR that leads to this high level of selection. Newly developed TCR motif algorithms identified a lysine at position 1 of the CDR3? motif that is highly conserved and likely important for antigen recognition. Crystal structure analysis of the YVL-BR/HLA-A2 complex revealed that the MHC-bound peptide bulges at position 4, exposing a negatively charged aspartic acid that may interact with the positively charged lysine of CDR3?. TCR cloning and site-directed mutagenesis of the CDR3? lysine ablated YVL-BR-tetramer staining and substantially reduced CD69 upregulation on TCR mutant-transduced cells following antigen-specific stimulation. Reduced activation of T cells expressing this CDR3 motif was also observed following exposure to mutated (D4A) peptide. In summary, we show that a highly public TCR repertoire to an immunodominant epitope of a common human virus is almost completely selected on the basis of CDR3? and provide a likely structural basis for the selection. These studies emphasize the importance of examining TCR?, as well as TCR?, in understanding the CD8 T cell receptor repertoire.

Dataset Information

TCR? repertoire of CD4+ and CD8+ T cells is distinct in richness, distribution, and CDR3 amino acid composition.

Publications

TCRβ repertoire of CD4+ and CD8+ T cells is distinct in richness, distribution, and CDR3 amino acid composition.

Similar Datasets

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