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Naive CD8? T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics.

ABSTRACT: Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8(+) T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment.

SUBMITTER: Neller MA

PROVIDER: S-EPMC4533101 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Naive CD8⁺ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics.

Neller Michelle A MA Ladell Kristin K McLaren James E JE Matthews Katherine K KK Gostick Emma E Pentier Johanne M JM Dolton Garry G Schauenburg Andrea J A AJ Koning Dan D Fontaine Costa Ana Isabel C A AI Watkins Thomas S TS Venturi Vanessa V Smith Corey C Khanna Rajiv R Miners Kelly K Clement Mathew M Wooldridge Linda L Cole David K DK van Baarle Debbie D Sewell Andrew K AK Burrows Scott R SR Price David A DA Miles John J JJ

Immunology and cell biology 20150324 7

Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8(+) T-cell precursor populations specific for a range o ...[more]

PMID: 25801351

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Project description:Among Immunotherapeutic approaches for cancer treatment, the adoptive transfer of antigen specific T cells is still a relevant approach, that could have higher efficacy when further combined with immune check-point blockade. A high number of adoptive transfer trials have been performed in metastatic melanoma, due to its high immunogenic potential, either with polyclonal TIL or antigen-specific polyclonal populations. In this setting, the extensive characterization of T cell functions and receptor diversity of infused polyclonal T cells is required, notably for monitoring purposes. We developed a clinical grade procedure for the selection and amplification of polyclonal CD8 T cells, specific for two shared and widely expressed melanoma antigens: Melan-A and MELOE-1. This procedure is currently used in a clinical trial for HLA-A2 metastatic melanoma patients. In this study, we characterized the T-cell diversity (T-cell repertoire) of such T cell populations using a new RNAseq strategy. We first assessed the added-value of TCR receptor sequencing, in terms of sensitivity and specificity, by direct comparison with cytometry analysis of the T cell populations labeled with anti-Vß-specific antibodies. Results from these analyzes also confirmed specific features already reported for Melan-A and MELOE-1 specific T cell repertoires in terms of V-alpha recurrence usage, on a very high number of T cell clonotypes. Furthermore, these analyses also revealed undescribed features, such as the recurrence of a specific motif in the CDR3? region for MELOE-1 specific T cell repertoire. Finally, the analysis of a large number of T cell clonotypes originating from various patients revealed the existence of public CDR3? and ß clonotypes for Melan-A and MELOE-1 specific T cells. In conclusion, this method of high throughput TCR sequencing is a reliable and powerful approach to deeply characterize polyclonal T cell repertoires, and to reveal specific features of a given TCR repertoire, that would be useful for immune follow-up of cancer patients treated by immunotherapeutic approaches.

Dataset Information

Naive CD8? T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics.

Publications

Naive CD8⁺ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics.

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