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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.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.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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Response of the system to clonal perturbation.The system was initialized at steady state, and was subjected to thesudden enlargement of a single randomly chosen clone by 10,000-fold.This clone was held artificially high for 10 days, after which thesystem was allowed to relax back to steady-state. The artificiallyenlarged clone consumes TCR-non-specific resources at a rate appropriateto its size. The TCR repertoire diversity is shown in the bottom panel,the T cell concentration is shown in the panel above.  varies as indicated. The variability un the steadystate diversity is due to the inherent variability in the system ratherthan to the imposed changes in .
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pcbi-1000396-g006: Response of the system to clonal perturbation.The system was initialized at steady state, and was subjected to thesudden enlargement of a single randomly chosen clone by 10,000-fold.This clone was held artificially high for 10 days, after which thesystem was allowed to relax back to steady-state. The artificiallyenlarged clone consumes TCR-non-specific resources at a rate appropriateto its size. The TCR repertoire diversity is shown in the bottom panel,the T cell concentration is shown in the panel above. varies as indicated. The variability un the steadystate diversity is due to the inherent variability in the system ratherthan to the imposed changes in .

Mentions: We start with a system at steady state, and suddenly increase the size of asingle clone by a factor of 104, allowing it to consume the non-TCRspecific resources its new size requires. The diversity decreases as a result.Over a few days, the other clones adjust to the new steady state. After ten dayswe remove the artificial support for the enlarged clone and allow the system toreturn to steady state (Figure6). We ran this experiment using models with four values ofρ differing over four orders of magnitude. For highρ, corresponding to a high competition for specificsignals, the diversity decreases less than in the absence of intra-clonalcompetition. Moreover, after the perturbation is resolved, the diversityincreases back to its steady-state, pre-perturbation value at a rate thatdepends very sensitively on . The return to steady-state diversity is more rapid thegreater the competition for TCR-specific signals. The estimated values for obtained from the DiGeorge patients implies a diversity-returntime on the order of a few days, rather than weeks or more.


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)

Response of the system to clonal perturbation.The system was initialized at steady state, and was subjected to thesudden enlargement of a single randomly chosen clone by 10,000-fold.This clone was held artificially high for 10 days, after which thesystem was allowed to relax back to steady-state. The artificiallyenlarged clone consumes TCR-non-specific resources at a rate appropriateto its size. The TCR repertoire diversity is shown in the bottom panel,the T cell concentration is shown in the panel above.  varies as indicated. The variability un the steadystate diversity is due to the inherent variability in the system ratherthan to the imposed changes in .
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000396-g006: Response of the system to clonal perturbation.The system was initialized at steady state, and was subjected to thesudden enlargement of a single randomly chosen clone by 10,000-fold.This clone was held artificially high for 10 days, after which thesystem was allowed to relax back to steady-state. The artificiallyenlarged clone consumes TCR-non-specific resources at a rate appropriateto its size. The TCR repertoire diversity is shown in the bottom panel,the T cell concentration is shown in the panel above. varies as indicated. The variability un the steadystate diversity is due to the inherent variability in the system ratherthan to the imposed changes in .
Mentions: We start with a system at steady state, and suddenly increase the size of asingle clone by a factor of 104, allowing it to consume the non-TCRspecific resources its new size requires. The diversity decreases as a result.Over a few days, the other clones adjust to the new steady state. After ten dayswe remove the artificial support for the enlarged clone and allow the system toreturn to steady state (Figure6). We ran this experiment using models with four values ofρ differing over four orders of magnitude. For highρ, corresponding to a high competition for specificsignals, the diversity decreases less than in the absence of intra-clonalcompetition. Moreover, after the perturbation is resolved, the diversityincreases back to its steady-state, pre-perturbation value at a rate thatdepends very sensitively on . The return to steady-state diversity is more rapid thegreater the competition for TCR-specific signals. The estimated values for obtained from the DiGeorge patients implies a diversity-returntime on the order of a few days, rather than weeks or more.

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.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.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