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

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. 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.

Figure 2. Spectratype data.

Raw CD4+ spectratype data (upper panel) for subject 1 on days 70 (left) and 183 (right) post-transplantation. CD4+ TCRBV usage frequency for average over 10 healthy controls (solid bars), and subject 1 (striped bars) on the same two days. The raw spectratype profiles are not represented on a consistent scale. Assays that had no peaks above 500 fluorescent units are routinely excluded from subsequent analysis. These are marked with an asterisk.

Figure 3. Best fit to the data.

Maximum-likelihood fits of the population-dynamic model given by Eqs.(1,4) to patient data. The curves are the trajectories of and , respectively.

Figure 4. 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.

Figure 5. Sensitivity curves.

Relative sensitivity trajectories for the model fit to data from subject 1. The left panel shows the relative sensitivity to changes inρ; the right panel shows the relative sensitivity to changes in , the maximum thymic emigration rate. Blue curves give the model solutions forc0+θT; red curves give the model solutions for the (unbiased) TCR repertoire diversity.

Figure 6. Response of the system to clonal perturbation.

The system was initialized at steady state, and was subjected to the sudden enlargement of a single randomly chosen clone by 10,000-fold. This clone was held artificially high for 10 days, after which the system was allowed to relax back to steady-state. The artificially enlarged clone consumes TCR-non-specific resources at a rate appropriate to 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 steady state diversity is due to the inherent variability in the system rather than to the imposed changes in .