High-throughput and high-dimensional single-cell analysis of antigen-specific CD8+ T cells

Ma, Ke-Yue; Schonnesen, Alexandra A.; He, Chenfeng; Xia, Amanda Y.; Sun, Eric; Chen, Eunise; Sebastian, Katherine R.; Guo, Yuwan; Balderas, Robert; Kulkarni-Date, Mrinalini; Jiang, Ning

doi:10.1038/s41590-021-01073-2

Cited by 49 publications

(39 citation statements)

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“…scTCRseq technology enables linking individual T-cell clones with their gene expression profiles, allowing an improved immunological interpretation of the TCR repertoire. Moreover, high-throughput identification of antigen-specific T cells is becoming possible by combining scTCRseq and DNA-barcoded peptide-MHC multimer technology (56,67,68). While scTCRseq provides a more precise characterization of individual clones, the number of T-cell clones that can be analyzed per sample is only the "tip of the iceberg" of the TCR repertoire.…”

Section: Discussionmentioning

confidence: 99%

“…With the advancements in single-cell analysis, more highthroughput scTCRseq methods are being developed, which can be roughly divided into two types: (1) methods reconstructing TCR sequences by extracting TCR reads from standard scRNAseq data and (2) those amplifying TCR genes selectively from the scRNAseq library and sequencing both the TCR gene and scRNAseq libraries. Experimental overview and characteristics of these two categories of scTCRseq methods are summarized in Figure 3 and Tables 2, 5 (17,18,55,56).…”

Section: Overview Of Single-cell Tcr Sequencing Methodsmentioning

confidence: 99%

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Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis

et al. 2022

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CD8+ T cells are the key effector cells that contribute to the antitumor immune response. They comprise various T-cell clones with diverse antigen-specific T-cell receptors (TCRs). Thus, elucidating the overall antitumor responses of diverse T-cell clones is an emerging challenge in tumor immunology. With the recent advancement in next-generation DNA sequencers, comprehensive analysis of the collection of TCR genes (TCR repertoire analysis) is feasible and has been used to investigate the clonal responses of antitumor T cells. However, the immunopathological significance of TCR repertoire indices is still undefined. In this review, we introduce two approaches that facilitate an immunological interpretation of the TCR repertoire data: inter-organ clone tracking analysis and single-cell TCR sequencing. These approaches for TCR repertoire analysis will provide a more accurate understanding of the response of tumor-specific T cells in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Overview Of Single-cell Tcr Sequencing Methodsmentioning

confidence: 99%

Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis

et al. 2022

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“…To our knowledge, no ASI clinical trial with T1D patients has examined the frequency of naïve T cell precursors in a patient’s PBMC that was capable of recognizing the ASI’s antigen prior to initiating the treatment. A number of studies have indicated that direct assessment of the frequency of human antigen-specific naïve T cells is feasible [ 8 , 45 , 46 , 47 , 48 , 49 , 50 ]. This may provide key information for helping to understand responsiveness vs. non-responsiveness to a particular ASI treatment.…”

Section: Discussionmentioning

confidence: 99%

Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases—The Case for Using Ignored Target Cell Antigen Determinants

Tian

Song

Kaufman

2022

Cells

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We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2–12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15–16 week old mice, insulin B-chain9-23/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPIL4-20/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual’s naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.

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“…Alternatively, TILs have been expanded in vitro using CD40activated B cells and then screened for reactivity to different neoantigens [93]. Another approach is to combine tetramer reagents [94,95] or dextramer reagents [96] with TCR sequencing to simultaneously detect the TCR sequence, transcriptome, and antigen-binding capabilities with single cell resolution. This can be done by either FACS-based sorting on T cells that can bind tetramer or dextramer before performing single cell sequencing (using fluorescently labeled reagents) or by detecting the tetramer or dextramer computationally after sequencing (using DNA-barcoded reagents.…”

Section: Box 1 Limitations Of the Barcode Methodsmentioning

confidence: 99%

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

Pauken¹,

Lagattuta²,

Lu³

et al. 2022

Trends in Immunology

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High-throughput and high-dimensional single-cell analysis of antigen-specific CD8+ T cells

Cited by 49 publications

References 50 publications

Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis

Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis

Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases—The Case for Using Ignored Target Cell Antigen Determinants

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

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