Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

Elhanati, Yuval; Sethna, Zachary; Callan, Curtis G.; Mora, Thierry; Walczak, Aleksandra M.

doi:10.1111/imr.12665

Cited by 126 publications

(178 citation statements)

References 67 publications

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“…Of the 80 million unique TCR

chains (defined by V-gene family and CDR3 sequence) in the 666 cohort repertoires, about 11 million chains are found in at least two individuals and referred to here as public chains (for a more nuanced examination of TCR chain sharing see [ Elhanati et al, 2018 ]). The occurrence patterns of these public TCR

s—the subset of subjects in which each distinct chain occurs—can be thought of as forming a very large binary matrix

with about 11 million rows and 666 columns.…”

Section: Resultsmentioning

confidence: 99%

Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

DeWitt

Smith

Schoch

et al. 2018

eLife

127

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The T cell receptor (TCR) repertoire encodes immune exposure history through the dynamic formation of immunological memory. Statistical analysis of repertoire sequencing data has the potential to decode disease associations from large cohorts with measured phenotypes. However, the repertoire perturbation induced by a given immunological challenge is conditioned on genetic background via major histocompatibility complex (MHC) polymorphism. We explore associations between MHC alleles, immune exposures, and shared TCRs in a large human cohort. Using a previously published repertoire sequencing dataset augmented with high-resolution MHC genotyping, our analysis reveals rich structure: striking imprints of common pathogens, clusters of co-occurring TCRs that may represent markers of shared immune exposures, and substantial variations in TCR-MHC association strength across MHC loci. Guided by atomic contacts in solved TCR:peptide-MHC structures, we identify sequence covariation between TCR and MHC. These insights and our analysis framework lay the groundwork for further explorations into TCR diversity.

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“…Of the 80 million unique TCR

s—the subset of subjects in which each distinct chain occurs—can be thought of as forming a very large binary matrix

with about 11 million rows and 666 columns.…”

Section: Resultsmentioning

confidence: 99%

Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

DeWitt

Smith

Schoch

et al. 2018

eLife

127

View full text Add to dashboard Cite

show abstract

“…On Tregs, the TCR exists as an alpha-beta heterodimer that is restricted to antigens presented by MHCII [ 23 ]. There is a great diversity in the specificity of TCRs due to somatic V(D)J recombination in the thymus, which has the capacity to generate in humans up to 10 61 different TCR sequences [ 24 ]. High affinity TCRs on Treg cells are known to elicit a strong response to self-peptides as a result of thymic T cell selection selecting for Tregs with high-affinity, self-peptide recognising TCRs.…”

Section: The Regulatory T Cellmentioning

confidence: 99%

Treg Enhancing Therapies to Treat Autoimmune Diseases

Eggenhuizen

Ooi

2020

IJMS

172

109

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Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

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“…To further examine the genetic influence on the TCR repertoire formation, we analyzed the TCR chain sequences that are shared among donors at the amino acid level. The reidentification of clonotypes in a second sample depends on the overall TCR diversity and is therefore limited by the number of cells sequenced and the frequency of a given sequence within a sample (38). To determine chains chains pairs whether our sample size of 30,000 to 40,000 sequences out of about 1 million cells is sufficient to detect identical sequences and to develop an upper boundary of detection, we first performed experiments on replicate total T cell samples taken from the same individual (Fig.…”

Section: Lack Of Evidence For Major Structural Constraints In Tcr α-βmentioning

confidence: 99%

Determinants governing T cell receptor α/β-chain pairing in repertoire formation of identical twins

Tanno

Gould

McDaniel

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and β-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α–β pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαβ dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR β-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαβ amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαβ in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α–β pairs with entire sequence identities.

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Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

Cited by 126 publications

References 67 publications

Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

Treg Enhancing Therapies to Treat Autoimmune Diseases

Determinants governing T cell receptor α/β-chain pairing in repertoire formation of identical twins

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