A new mechanism shapes the naïve CD8+ T cell repertoire: the selection for full diversity

Gonçalves, Pedro; Ferrarini, Marco; Molina-Parı́s, Carmen; Lythe, Grant; Vasseur, Florence; Lim, Annik; Rocha, Bénédita; Azogui, Orly

doi:10.1016/j.molimm.2017.01.026

Cited by 20 publications

(34 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, we injected 1.5x10 6 CD4 + and CD8 + T cells per mouse, whereas other studies used from 3-4x10 6 [6, 7, 9, 13] to up to 1.5x10 7 T cells per mouse [15, 21]. The latter numbers approach the total number of CD8 + T cells present in B6 mice (2x10 7 ) [34]. The injection of low numbers of T and DC precursors was necessary to clearly visualize cell interactions.…”

Section: Resultsmentioning

confidence: 99%

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

et al. 2017

Self Cite

View full text Add to dashboard Cite

CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We show that in contrast to CD4+ T cells which form transient contacts with Ag+DC, CD8+ T cells form immediate stable contacts and activate the Ag+DC, acquire fragments of the DC membranes by trogocytosis, leading to their acquisition of some of the DC properties. They express MHC class II, and become able to present the specific Marilyn peptide to naïve Marilyn CD4+ T cells, inducing their extensive division. In vivo, these CD8+ T cells form direct stable contacts with motile naïve CD4+ T cells, recruiting them to Ag+DC binding and to the formation of ternary complexes, where CD4+ and CD8+ T cells interact with the DC and with one another. The presence of CD8+ T cells during in vivo immune responses leads to the early activation and up-regulation of multiple functions by CD4+ T lymphocytes. Thus, while CD4+ T cell help is important to CD8+ T cell responses, CD8+ T cells can interact directly with naïve CD4+ T cells impacting their recruitment and differentiation.

show abstract

Section: Resultsmentioning

confidence: 99%

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other hand, it is possible to obtain all major organs from mice of various ages, albeit only once per mouse. Accurate cell counts are limited by the difficulty of extracting and separating T cells whilst avoiding, or at least keeping a strict account of, losses at various stages of purification …”

Section: How Many Tcr Clonotypes Are Maintained?mentioning

confidence: 99%

“…Suppose that an unbiased random sample of m cells is taken, and sequenced, from a total repertoire of S cells. Let us start with the probability that one particular cell in the repertoire is part of the sample:

q = \frac{m}{S} .

In naïve repertoire single‐cell sequencing q ≪ 1, because m , approximately 10 2 –10 3 , is much smaller than S , approximately 10 7 (mice) or 10 11 (humans). We seek a relationship between n i , the number of cells of type i in the repertoire, and s i , the number of cells of type i in the sample.…”

Section: How Many Tcr Clonotypes Are Maintained?mentioning

confidence: 99%

See 1 more Smart Citation

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

Lythe

Molina-Parı́s

2018

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Computational and mathematical models can provide a means to further investigate these associations for potential causal relationships. A study by Goncalves et al [44] provides a recent example. Mathematical analysis of single-cell TCRβ expression of naïve CD8+ T cells motivated the proposal of a new selection mechanism that strongly selects for complete TCRβ-chain diversity.…”

Section: How Computational and Mathematical Models Can Help Us Decodementioning

confidence: 99%

The expanding role of systems immunology in decoding the T cell receptor repertoire

Venturi¹

2018

Current Opinion in Systems Biology

View full text Add to dashboard Cite

T cells play a crucial role in the immune system’s defense against many infectious diseases, including persistent infections for which no effective vaccines currently exist. The T cell component of the adaptive immune system is highly complex involving a constantly evolving landscape of various inter-related T cell populations. These T cell populations are characterized by their phenotypic and functional properties as well as the collection, or repertoire, of T cell receptors (TCR) that mediate T cell recognition of antigenic peptides derived from pathogens. Understanding the various processes and factors that impact the development and evolution of the broader T cell repertoire available to recognize and respond to pathogens and the characteristics of antigen-experienced T cell repertoires associated with effective immune control of pathogens is critical to the rational design of T cell-based vaccines and therapies. In this article we discuss, using examples of recent research, the promise that systems immunology approaches, involving quantitative analysis and mathematical and computational modeling of immunological data, hold for decoding the complex TCR repertoire system in the current era of advancing technologies.

show abstract

A new mechanism shapes the naïve CD8+ T cell repertoire: the selection for full diversity

Cited by 20 publications

References 95 publications

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

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

The expanding role of systems immunology in decoding the T cell receptor repertoire

Contact Info

Product

Resources

About