TCR-sequencing in cancer and autoimmunity: barcodes and beyond

Pauken, Kristen E.; Lagattuta, Kaitlyn A.; Lu, Benjamin Y.; Lucca, Liliana E.; Daud, Adil; Hafler, David A.; Kluger, Harriet M.; Raychaudhuri, Soumya; Sharpe, Arlene H.

doi:10.1016/j.it.2022.01.002

Cited by 32 publications

(19 citation statements)

References 145 publications

(252 reference statements)

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“…This report analyzed the amino acid sequence of over 100 million TCR CDR3 beta chains from over 1,000 subjects. Since both TCR chains contribute to antigen specificity, we would have wished to extend our analyses to CDR3aa alpha/beta pairs obtained through single-cell studies ( Pauken et al., 2022 ). However, there is no available dataset that contains paired CDR3 alpha and beta chains from large human cohorts.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is no available dataset that contains paired CDR3 alpha and beta chains from large human cohorts. Indeed, because of methodological constraints inherent to single-cell approaches, paired CDR3 alpha and beta chain sequencing has been limited to small numbers of subjects, typically 1 to 15 ( Fischer et al., 2020 ; Pauken et al., 2022 ; Tanno et al., 2020 ). Focusing on CDR3 amino acid sequences instead of nucleotides and V/J gene usage allowed us to uncover more numerous public and superpublic CDR3aa than anticipated, since this analysis considers synonymous codons.…”

Section: Discussionmentioning

confidence: 99%

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Two types of human TCR differentially regulate reactivity to self and non-self antigens

Trofimov¹,

Brouillard²,

Séguin³

et al. 2022

iScience

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Trofimov¹,

Brouillard²,

Séguin³

et al. 2022

iScience

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“…However, there is no available dataset that contains paired CDR3 alpha and beta chains from large human cohorts. Indeed, because of methodological constraints inherent to single-cell approaches, paired CDR3 alpha and beta chain sequencing has been limited to small numbers of subjects, typically 1 to 15 (Fischer et al, 2020; Pauken et al, 2022; Tanno et al, 2020). Focusing on CDR3 amino acid sequences instead of nucleotides and V/J gene usage allowed us to uncover more numerous public and superpublic CDR3aa than anticipated, since this analysis considers synonymous codons.…”

Section: Discussionmentioning

confidence: 99%

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Trofimov

Brouillard

Séguin

et al. 2022

Preprint

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SUMMARYBased on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist throughout life, are highly shared among subjects, and are polyreactive to self and microbial antigens. Thus, >50% of cord blood TCRs are responsive to SARS-CoV2 and other common pathogens. TDT- dependent TCRs present distinct structural features and are less shared among subjects. TDT- dependent TCRs are produced in maximal numbers during infancy when thymic output and TDT activity reach a summit, are more abundant in subjects with AIRE mutations, and seem to play a dominant role in graft-versus-host disease. Factors decreasing thymic output (age, male sex) negatively impact TCR diversity. Males compensate for their lower repertoire diversity via hyperexpansion of selected TCR clonotypes.

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“…T-cells activation is triggered by an antigen-specific signal and a co-stimulatory cue due to the CD28 binding by T-cells to B7 ligands on the antigen presenting cells (APCs) [ 15 ]. Following their activation in the periphery, T-cells start to proliferate and undergo clonal expansion [ 4 ], generating a population of expanded T-cell clones (clonotypes) that share the same TCR sequences conserved during mature T-lymphocytes mitosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the TCR repertoire footprint dynamically evolves according to the challenges with which the immune system is confronted [ 4 ], such as infections, aging, autoimmune diseases, cancer and many other stimuli. Importantly, the exposure to an antigen triggers a massive expansion of antigen-specific T-cells, altering the composition of the TCR repertoire in favor of specific clonotypes (TCR bias) [ 26 , 27 ] that can be correlated to a biological process and exploited as “molecular barcodes” both in health and diseases [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

Mazzotti

Gaimari

Bravaccini

et al. 2022

IJMS

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The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers’ choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago.

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TCR-sequencing in cancer and autoimmunity: barcodes and beyond

Cited by 32 publications

References 145 publications

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Two types of human TCR differentially regulate reactivity to self and non-self antigens

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

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