Genetic and environmental determinants of human TCR repertoire diversity

Krishna, Chirag; Chowell, Diego; Gönen, Mithat; Elhanati, Yuval; Chan, Timothy A.

doi:10.1186/s12979-020-00195-9

Cited by 48 publications

(56 citation statements)

References 56 publications

(71 reference statements)

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“…Mechanistically, CD8 + T cells may be more susceptible to activation, possibly due to the more widespread expression of MHC class I vs class II molecules or an intrinsic limitation in maintaining quiescence (107). Additional epigenetic hallmarks of CD8 + T cell aging are the inaccessibility to regulatory regions of genes involved in basic cellular functions, such as the mitochondrial respiratory genes (106).…”

Section: Accepted Articlementioning

confidence: 99%

Hallmarks of the aging T‐cell system

2021

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The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7 th-10 th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Ageassociated changes occur at the level of the T cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.

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Section: Accepted Articlementioning

confidence: 99%

Hallmarks of the aging T‐cell system

2021

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“…We additionally show that HLA zygosity of an individual does not strongly affect the overall diversity of their TCRβ repertoire. While previous work with a similar dataset found a correlation between HLA class I zygosity and decreased repertoire richness among CMV-individuals, that analysis quantified diversity with different metrics and did not control for sampling depth, which could impact the finding (30). One limitation of this cohort is that over half of the individuals are of European descent, and a more diverse cohort may have a different distribution of HLA zygosities.…”

Section: Discussionmentioning

confidence: 93%

“…To characterize the expanded repertoire of each subject, we selected the top 5,000 unique clones by frequency from each full repertoire prior to downsampling. As chronic infections such as CMV increase the clonality of TCRβ repertoires (11,30)…”

Section: Sharing Of the Low Frequency And Expanded Tcrβ Clones Is Impmentioning

confidence: 99%

HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

Gittelman

et al. 2021

Preprint

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The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, certain factors such as low junctional diversity, thymic selection, and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCRβ variable region of 426 healthy individuals, we find that fewer than 1% of TCRβ clones are shared between individuals on average, consistent with largely private TCRβ repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCRβ clones, with each additional shared HLA allele contributing to an increase in ~0.01% of the total TCRβ clones being shared, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCRβ clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCRβ clone sharing, indicating that the pattern of private TCRβ clonal expansion is a general feature of the T-cell response to other infectious antigens. All of these factors contribute to shaping the TCRβ repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

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“…In this study, no distinction could be made between TCR genes of CD4+ and CD8+ T cells in vascular tissues ( 75 ). Most importantly, patients and controls in these studies investigating TCR diversity were not controlled for CMV status or matched for HLA polymorphisms, factors associated with TCR diversity ( 76 ). Thus, it remains to be identified whether CD8+ T cells are clonally expanded by a response toward shared self or foreign antigens, such as derived from infectious agents.…”

Section: Phenotype Of Cd8+ T Cells In Circulation and Affected Tissuementioning

confidence: 99%

CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

et al. 2021

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Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.

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Genetic and environmental determinants of human TCR repertoire diversity

Cited by 48 publications

References 56 publications

Hallmarks of the aging T‐cell system

Hallmarks of the aging T‐cell system

HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

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