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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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Clone sizes, T cell concentrations and TCR repertoire diversity.Clone sizes over time as computed under the model of Eqs.(1,4)                            (A–C) and the corresponding T cell concentrations (D) and TCR                            repertoire diversity (E) as a function of time past transplantation.                            computed under the model of Eqs.(1,4) as a function of time past                            transplantation. Parameter  (see Model section) is varied as                            indicated while all other parameters are held constant. The higher , the more limiting are TCR-specific resources.                            “Emigrant number” refers to the order in which                            clones leave the thymus and enter the periphery; emigrant number 1 is                            the first clone to arise, etc.
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pcbi-1000396-g001: Clone sizes, T cell concentrations and TCR repertoire diversity.Clone sizes over time as computed under the model of Eqs.(1,4) (A–C) and the corresponding T cell concentrations (D) and TCR repertoire diversity (E) as a function of time past transplantation. computed under the model of Eqs.(1,4) as a function of time past transplantation. Parameter (see Model section) is varied as indicated while all other parameters are held constant. The higher , the more limiting are TCR-specific resources. “Emigrant number” refers to the order in which clones leave the thymus and enter the periphery; emigrant number 1 is the first clone to arise, etc.

Mentions: To illustrate the connection between these alternative homeostatic mechanisms and the observations one might make on the DiGeorge subjects, consider the following two scenarios as a thought experiment. First, suppose that TCR-specific resources such as spMHC are not limiting, either because they are produced in great excess or because they are rendered unnecessary. Under these conditions, homeostasis will be due exclusively to competition for TCR-nonspecific resources. The first T cells leaving the thymus will expand rapidly, consuming the TCR-nonspecific resources required for growth of their own growth and for the growth of all other clones. Subsequent T cells leaving the thymus will encounter a more impoverished environment and will grow more slowly, leading to early dominance of one or a small number of early clones and therefore a limited TCR repertoire (Figure 1). Conversely, if TCR-nonspecific resources such as cytokines were not limiting, and that homeostasis therefore depended solely on competition for TCR-specific signaling, the only cellular competition would be among T cells of the same clonotype. In this case, each clone will grow to roughly the same self-limiting size regardless of when its founder emigrates from the thymus. In this case, TCR repertoire diversity will grow at the greatest possible rate, all other things being equal (Figure 1).


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)

Clone sizes, T cell concentrations and TCR repertoire diversity.Clone sizes over time as computed under the model of Eqs.(1,4)                            (A–C) and the corresponding T cell concentrations (D) and TCR                            repertoire diversity (E) as a function of time past transplantation.                            computed under the model of Eqs.(1,4) as a function of time past                            transplantation. Parameter  (see Model section) is varied as                            indicated while all other parameters are held constant. The higher , the more limiting are TCR-specific resources.                            “Emigrant number” refers to the order in which                            clones leave the thymus and enter the periphery; emigrant number 1 is                            the first clone to arise, etc.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000396-g001: Clone sizes, T cell concentrations and TCR repertoire diversity.Clone sizes over time as computed under the model of Eqs.(1,4) (A–C) and the corresponding T cell concentrations (D) and TCR repertoire diversity (E) as a function of time past transplantation. computed under the model of Eqs.(1,4) as a function of time past transplantation. Parameter (see Model section) is varied as indicated while all other parameters are held constant. The higher , the more limiting are TCR-specific resources. “Emigrant number” refers to the order in which clones leave the thymus and enter the periphery; emigrant number 1 is the first clone to arise, etc.
Mentions: To illustrate the connection between these alternative homeostatic mechanisms and the observations one might make on the DiGeorge subjects, consider the following two scenarios as a thought experiment. First, suppose that TCR-specific resources such as spMHC are not limiting, either because they are produced in great excess or because they are rendered unnecessary. Under these conditions, homeostasis will be due exclusively to competition for TCR-nonspecific resources. The first T cells leaving the thymus will expand rapidly, consuming the TCR-nonspecific resources required for growth of their own growth and for the growth of all other clones. Subsequent T cells leaving the thymus will encounter a more impoverished environment and will grow more slowly, leading to early dominance of one or a small number of early clones and therefore a limited TCR repertoire (Figure 1). Conversely, if TCR-nonspecific resources such as cytokines were not limiting, and that homeostasis therefore depended solely on competition for TCR-specific signaling, the only cellular competition would be among T cells of the same clonotype. In this case, each clone will grow to roughly the same self-limiting size regardless of when its founder emigrates from the thymus. In this case, TCR repertoire diversity will grow at the greatest possible rate, all other things being equal (Figure 1).

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