How many TCR clonotypes does a body maintain?

Lythe, Grant; Callard, Robin E.; Hoare, Rollo L.; Molina-Parı́s, Carmen

doi:10.1016/j.jtbi.2015.10.016

Cited by 157 publications

(166 citation statements)

References 120 publications

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“…Qi et al (2014) used an incidence-based nonparametric approach analyzing multiple independent blood samples from each individual and the Chao 2 estimator and arrived at minimal estimates of 50 to 100 million different TRB gene sequences for both naive CD4 + and CD8 + T cells in young adults. This estimate is consistent with TREC frequencies as well as with modeling experiments which predict that the number of distinct sequences in humans is by only one order of magnitude lower than the number of total naive cells (Lythe et al, 2016). …”

Section: Age and The Naive T Cell Receptor Repertoire: How Much Diversupporting

confidence: 87%

Successful and Maladaptive T Cell Aging

2017

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Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Here we review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms. Processes include homeostatic proliferation that maintains compartment size at the expense of partial loss in stemness and incomplete differentiation and the activation of negative regulatory programs, which constrain effector T cell expansion and prevent increasing oligoclonality but also interfere with memory cell generation. We propose that immune failure occurs when adaptive strategies developed by the aging T cell system fail and also discuss how, in some settings, the programs associated with T cell aging culminates in a maladaptive response that directly contributes to chronic inflammatory disease.

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Section: Age and The Naive T Cell Receptor Repertoire: How Much Diversupporting

confidence: 87%

Successful and Maladaptive T Cell Aging

2017

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“…With thymic output and peripheral division constant then, as well as a mean steady‐state number of cells, there is a well‐defined mean steady‐state number of clonotypes, N * , equal to the product of θ and the mean lifetime of a clonotype in the periphery. In the limit

n_{θ} α \to 0

N^{*} \to N_{ss} α false[1 - γ_{E} - log (n_{θ} α) false],

where γ E = 0.577… is the Euler‐Mascheroni constant …”

Section: Models Of Clonal Survivalmentioning

confidence: 99%

Some deterministic and stochastic mathematical models of naïve T‐cell homeostasis

Lythe

Molina-Parı́s

2018

Immunological Reviews

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Humans live for decades, whereas mice live for months. Over these long timescales, naïve T cells die or divide infrequently enough that it makes sense to approximate death and division as instantaneous events. The population of T cells in the body is naturally divided into clonotypes; a clonotype is the set of cells that have identical T-cell receptors. While total numbers of cells, such as naïve CD4 T cells, are large enough that ordinary differential equations are an appropriate starting point for mathematical models, the numbers of cells per clonotype are not. Here, we review a number of basic mathematical models of the maintenance of clonal diversity. As well as deterministic models, we discuss stochastic models that explicitly track the integer number of naïve T cells in many competing clonotypes over the lifetime of a mouse or human, including the effect of waning thymic production. Experimental evaluation of clonal diversity by bulk high-throughput sequencing has many difficulties, but the use of single-cell sequencing is restricted to numbers of cells many orders of magnitude smaller than the total number of T cells in the body. Mathematical questions associated with extrapolating from small samples are therefore key to advances in understanding the diversity of the repertoire of T cells. We conclude with some mathematical models on how to advance in this area.

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“…Assuming a significant role for spMHC niche‐based competition, several studies have modeled the within‐host evolution of TCR clonal structure using stochastic birth‐death models. Lythe et al used a model of competition for a set of spMHC niches and estimate naive T‐cell clone sizes in humans to be of the order 10 cells, a result which is insensitive to the details of niche structure and level of TCR cross‐reactivity by construction. This result assumes a 1:25 ratio of thymic output to peripheral production, which is rather low compared to experimental estimates, at least in young adults (see above).…”

Section: Mature Naive T Cellsmentioning

confidence: 99%

The natural history of naive T cells from birth to maturity

Seddon

Yates

2018

Immunological Reviews

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Generating and maintaining a diverse repertoire of naive T cells is essential for protection against pathogens, and developing a mechanistic and quantitative description of the processes involved lies at the heart of our understanding of vertebrate immunity. Here, we review the biology of naive T cells from birth to maturity and outline how the integration of mathematical models and experiments has helped us to develop a full picture of their life histories.

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How many TCR clonotypes does a body maintain?

Cited by 157 publications

References 120 publications

Successful and Maladaptive T Cell Aging

Successful and Maladaptive T Cell Aging

Some deterministic and stochastic mathematical models of naïve T‐cell homeostasis

The natural history of naive T cells from birth to maturity

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