Identifying the inheritable component of human thymic T cell repertoire generation in monozygous twins

Heikkilä, Nelli; Vanhanen, Reetta; Yohannes, Dawit A.; Saavalainen, Päivi; Meri, Seppo; Jokiranta, T. Sakari; Jarva, Hanna; Mattila, Ilkka; Hamm, David; Sormunen, Silja; Saramäki, Jari; Arstila, T. Petteri

doi:10.1002/eji.201948404

Cited by 7 publications

(8 citation statements)

References 7 publications

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“…Two of the donors (A and B) were monozygotic twins. As previously reported, their TCR repertoires showed a genetic impact in the V and J gene usage and in the generation of junctional sequences, but not in thymic selection [15]. On average, we obtained 5.9 and 1.1 million unique TCRα and TCRβ nucleotide sequences, respectively.…”

Section: Tcr Clone Distribution In Thymus Samplessupporting

confidence: 66%

“…This may be due to the fact that HLA binding is mainly mediated by hypervariable loops encoded by germline sequences in the V genes, and thus likely to affect mostly V gene usage patterns [6]. Indeed, the aspect of TCR repertoire shown to be most strongly affected by heritable factors is TCR gene segment usage [13,15,45].…”

Section: Discussionmentioning

confidence: 99%

“…Six thymus resects were obtained from immunologically healthy infants undergoing corrective cardiac surgery for a congenital heart defect (aged 4-8 months, 2/6 were female). Two of the thymus donors (samples A and B) were monozygous twins and the genetic impact on the TCR repertoire has been analyzed previously [15]. Thymocytes were mechanically extracted from the resects and aliquots of 10 million thymocytes were stored as dry pellets in − 70 • C.…”

Section: Samplesmentioning

confidence: 99%

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Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Heikkilä¹,

Sormunen²,

Mattila³

et al.

immuneACCESS

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The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRβ chains with the estimated total TCR diversity of >10 8 . Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self-and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4 + compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRβ repertoire associated with these chains.

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Section: Tcr Clone Distribution In Thymus Samplessupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Samplesmentioning

confidence: 99%

See 1 more Smart Citation

Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Heikkilä¹,

Sormunen²,

Mattila³

et al.

immuneACCESS

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“…Many reports show that the TCR naive repertoire of twins is different [ 23 , 46 ]. Evaluation of the preselection diversity of the human T-cell repertoire can be performed via the quantification of VDJ recombinants with out-of-frame DNA sequences, as these sequences are not subject to selection and therefore reflect only the recombination process [ 47 ].…”

Section: Revisiting the Pathogen-based Hypothesis To Explain Mhc Poly...mentioning

confidence: 99%

COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution

Pontarotti

Paganini²

2022

IJMS

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We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.

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“…To discover the associations between genetic variation and TCR V gene usage, Sharon et al applied expression quantitative trait locus (eQTL) mapping in a large human cohort and discovered associations between variation in the HLA locus and TCR V gene usage (39). Other studies established increased similarity in V and J gene usage between identical twins in both peripheral (40) and thymic T cells (41), despite the overall similarity between any two individuals. A more recent study using single cell RNA sequencing elucidated further details about the process of V (D) J gene recombination and TCR a and b chain usage (20).…”

Section: Genetic Influences On Tcr Repertoire Selectionmentioning

confidence: 99%

High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

Khosravi‐Maharlooei

Sykes

2021

Front. Immunol.

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Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.

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Identifying the inheritable component of human thymic T cell repertoire generation in monozygous twins

Cited by 7 publications

References 7 publications

Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Generation of self-reactive, shared T-cell receptor α chains in the human thymus

COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution

High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

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