T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer

Mazzotti, Lucia; Gaimari, Anna; Bravaccini, Sara; Maltoni, Roberta; Cerchione, Claudio; Juan, Manel; Navarro, Europa Azucena-Gonzalez; Pasetto, Anna; Silva, Daniela; Ancarani, Valentina; Sambri, Vittorio; Calabrò, Luana; Martinelli, Giovanni; Mazza, M.

doi:10.3390/ijms23158590

Cited by 20 publications

(11 citation statements)

References 206 publications

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“…Adaptive immunity that involves antigen-specific responses is regulated by TCRs and B-cell receptors (BCRs) on T and B cells, respectively ( 49 ). Moreover, clonal expansion of B/T cells is a hallmark of antigen selection in diseases that may be captured via TCR and BCR sequencing ( 50 – 52 ). In addition to generating transcriptome sequences of single cells in PBMCs from young RMs infected as neonates using the single-cell immune profiling assay (10× Genomics) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection

Evangelous,

Berry,

Venkatayogi

et al. 2023

J Virol

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We recently found that a new pathogenic chimeric simian-human immunodeficiency virus (SHIV) elicited heterologous human immunodeficiency virus type-1 (HIV-1) neutralizing antibodies (nAbs) in therapy-naïve young rhesus macaques (RMs) following neonatal SHIV infection. Moreover, a subset of the SHIV-infected young RMs spontaneously controlled viremia. Here we evaluated humoral and cellular immunity and plasma biomarkers associated with spontaneous viremia suppression in a new model of young SHIV-infected RMs that generated heterologous HIV-1 nAbs independent of viremia control to gain insights into pediatric immunity that may be harnessed by appropriate therapies in HIV-1-infected infants and children. We determined the levels of 31 plasma analytes (cytokines, chemokines, and growth factors) in SHIV-infected RMs over the course of infection and found that six analytes with chemoattractant or pro-inflammatory activities had significantly lower levels in plasma of RMs that controlled viremia compared to non-controllers. Single-cell transcriptomics of blood-derived immune cells demonstrated that RMs with viremia control had upregulated genes associated with immune activation and cytotoxic functions, whereas non-controllers had upregulated genes associated with immune cell exhaustion and dysfunction. In addition to CD8 T and natural killer cells, monocytes with upregulation of inhibitory genes previously reported only in cytotoxic cells constituted the immunologic environment associated with viremia suppression. These data implicated a complex immunologic milieu of viremia suppression that is not fully defined in pediatric subjects. Understanding immune cell subsets that may be harnessed to control viremia will provide insights into future designs of HIV-1 therapeutic strategies. IMPORTANCE Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.

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Section: Resultsmentioning

confidence: 99%

Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection

Evangelous,

Berry,

Venkatayogi

et al. 2023

J Virol

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“…Targeted TCR sequencing is typically done using first a targeted amplification step with specific primers spanning the CDR3 region (72,73). For targeted TCR sequencing, the starting material can be either genomic DNA or cDNA depending on the context and has its own pros and cons (74). The first TCR repertoire analyses were done using bulk TCR sequencing.…”

Section: Tcr Sequencing Techniques Can Be Either Direct or Indirect D...mentioning

confidence: 99%

Antigen-specificity measurements are the key to understanding T cell responses

et al. 2023

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Antigen-specific T cells play a central role in the adaptive immune response and come in a wide range of phenotypes. T cell receptors (TCRs) mediate the antigen-specificities found in T cells. Importantly, high-throughput TCR sequencing provides a fingerprint which allows tracking of specific T cells and their clonal expansion in response to particular antigens. As a result, many studies have leveraged TCR sequencing in an attempt to elucidate the role of antigen-specific T cells in various contexts. Here, we discuss the published approaches to studying antigen-specific T cells and their specific TCR repertoire. Further, we discuss how these methods have been applied to study the TCR repertoire in various diseases in order to characterize the antigen-specific T cells involved in the immune control of disease.

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“…Sequencing the T cell receptors (TCRs) of TILs or lymphocytes found in peripheral blood provides crucial insights into the T-cell repertoire and their responses against neoantigens associated with tumors (22)(23)(24). This information holds paramount importance in identifying TCRs that specifically target these neoantigens.…”

Section: Introductionmentioning

confidence: 99%

The T Cell Receptor β Chain Repertoire of Tumor Infiltrating Lymphocytes Improves Neoantigen Prediction and Prioritization

Pham,

Nguyen,

Nguyen

et al. 2023

Preprint

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In the realm of cancer immunotherapy, the meticulous selection of neoantigens plays a fundamental role in enhancing personalized treatments. Traditionally, this selection process has heavily relied on predicting the binding of peptides to human leukocyte antigens (pHLA). Nevertheless, this approach often overlooks the dynamic interaction between tumor cells and the immune system. In response to this limitation, we have developed an innovative prediction algorithm rooted in machine learning, integrating T cell receptor β chain (TCRβ) profiling data from colorectal cancer (CRC) patients for a more precise neoantigen prioritization. TCRβ sequencing was conducted to profile the TCR repertoire of tumor-infiltrating lymphocytes (TILs) from 27 CRC patients. The data unveiled both intra-tumor and inter-patient heterogeneity in the TCRβ repertoires of CRC patients, likely resulting from the stochastic utilization of V and J segments in response to neoantigens. Our novel combined model integrates pHLA binding information with pHLA-TCR binding to prioritize neoantigens, resulting in heightened specificity and sensitivity compared to models using individual features alone. The efficacy of our proposed model was corroborated through ELISpot assays on long peptides, performed on four CRC patients. These assays demonstrated that neoantigen candidates prioritized by our combined model outperformed predictions made by the established tool NetMHCpan. This comprehensive assessment underscores the significance of integrating pHLA binding with pHLA-TCR binding analysis for more effective immunotherapeutic strategies.

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T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer

Cited by 20 publications

References 206 publications

Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection

Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection

Antigen-specificity measurements are the key to understanding T cell responses

The T Cell Receptor β Chain Repertoire of Tumor Infiltrating Lymphocytes Improves Neoantigen Prediction and Prioritization

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