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The dynamics of T-cell receptor repertoire diversity following thymus transplantation for DiGeorge anomaly.

Ciupe SM, Devlin BH, Markert ML, Kepler TB - PLoS Comput. Biol. (2009)

Bottom Line: Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire.Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation.The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational Immunology, Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA.

ABSTRACT
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRbeta V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.

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Best fit for constant ρ.Maximum-likelihood fit of data from subject 1 to the population-dynamic                            model given by Eqs.(1,4). The black curve represents the maximum                            likelihood solution; the orange and blue curves represent the maximum                            likelihood solutions subject to a constraint on  at the values indicated. The curves are the                            trajectories of  and , respectively.
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pcbi-1000396-g004: Best fit for constant ρ.Maximum-likelihood fit of data from subject 1 to the population-dynamic model given by Eqs.(1,4). The black curve represents the maximum likelihood solution; the orange and blue curves represent the maximum likelihood solutions subject to a constraint on at the values indicated. The curves are the trajectories of and , respectively.

Mentions: A reasonable concern is that thymic emigration rate and may be confounded–that it may be possible to compensate for smaller by making larger. We addressed that concern by performing a numerical experiment to determine the impact on the model fit of fixing outside the inferred credible bounds. We fix to be 10-fold smaller or larger than its maximum-likelihood estimate for subject 1. The fits are significantly worse (compare Figures 3 and 4), with log-likelihood ratios of about 8 in both cases (Table 3).


The dynamics of T-cell receptor repertoire diversity following thymus transplantation for DiGeorge anomaly.

Ciupe SM, Devlin BH, Markert ML, Kepler TB - PLoS Comput. Biol. (2009)

Best fit for constant ρ.Maximum-likelihood fit of data from subject 1 to the population-dynamic                            model given by Eqs.(1,4). The black curve represents the maximum                            likelihood solution; the orange and blue curves represent the maximum                            likelihood solutions subject to a constraint on  at the values indicated. The curves are the                            trajectories of  and , respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690399&req=5

pcbi-1000396-g004: Best fit for constant ρ.Maximum-likelihood fit of data from subject 1 to the population-dynamic model given by Eqs.(1,4). The black curve represents the maximum likelihood solution; the orange and blue curves represent the maximum likelihood solutions subject to a constraint on at the values indicated. The curves are the trajectories of and , respectively.
Mentions: A reasonable concern is that thymic emigration rate and may be confounded–that it may be possible to compensate for smaller by making larger. We addressed that concern by performing a numerical experiment to determine the impact on the model fit of fixing outside the inferred credible bounds. We fix to be 10-fold smaller or larger than its maximum-likelihood estimate for subject 1. The fits are significantly worse (compare Figures 3 and 4), with log-likelihood ratios of about 8 in both cases (Table 3).

Bottom Line: Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire.Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation.The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational Immunology, Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA.

ABSTRACT
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRbeta V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.

Show MeSH
Related in: MedlinePlus