Our current view of T cell differentiation and population dynamics is assembled from pieces of data obtained from separate experimental systems and is thus patchy. We reassessed homeostasis and dynamics of T cells 1) by generating a mathematical model describing the spatiotemporal features of T cell differentiation, and 2) by fitting this model to experimental data generated by disturbing T cell differentiation through transient depletion of dividing T cells in mice. This specific depletion was obtained by administration of ganciclovir to mice expressing the conditional thymidine kinase suicide gene in T cells. With this experimental approach, we could derive quantitative parameters describing the cell fluxes, residence times, and rates of import, export, proliferation, and death across cell compartments for thymocytes and recent thymic emigrants (RTEs). Among other parameters, we show that 93% of thymocytes produced before single-positive stages are eliminated through the selection process. Then, a postselection peripheral expansion of naive T cells contributes three times more to naive T cell production than the thymus, with half of the naive T cells consisting of dividing RTEs. Altogether, this work provides a quantitative population dynamical framework of thymocyte development, RTEs, and naive T cells.

Heterogeneity in the number of secondary cases caused per infectious individual is a plausible explanation for the observed skewness in genotypic cluster size distribution of TB.

Immunodeficiency following autologous CD34 ؉ -purified peripheral blood stem cell (PBSC) transplantation could be related to T-cell depletion of the graft or impaired T-cell reconstitution due to thymus irradiation. Aiming to assess the role of irradiated thymus in T-cell repopulation, we studied 32 adults with multiple myeloma, randomly assigned to receive high-dose therapy including total body irradiation (TBI) followed by autologous transplantation with either unselected or CD34 ؉ -selected PBSCs. The median number of reinfused CD3 ؉ cells was lower in the selected group (0.03 versus 14 ؋ 10 6 /kg; P ‫؍‬ .002). Lymphocyte subset counts were evaluated from month 3 to 24 after grafting. Naive CD4 ؉ T cells were characterized both by phenotype and by quantification of T-cell receptor rearrangement excision circles (TRECs). The reconstitution of CD3 ؉ and CD4 ؉ T cells was significantly delayed in the CD34 ؉ -selected group, but eventually led to counts similar to those found in the unselected group after month 12. Mechanism of reconstitution differed, however, between both groups. Indeed, a marked increase in the naive CD62L ؉ CD45RA ؉ CD4 ؉ subset was observed in the selected group, but not in the unselected group in which half of the CD45RA ؉ CD4 ؉ T cells appear to be CD62L ؊ . Age was identified as an independent adverse factor for CD4 ؉ and CD62L ؉ CD45RA ؉ CD4 ؉ T-cell reconstitution. Our results provide evidence that infusing PBSCs depleted of T cells after TBI in adults delays T-cell reconstitution but accelerates thymic regeneration.

The current Dutch BCG strategy, as well as the proposed inclusion of immigrant children from Turkey, Surinam and former Yugoslavia, is on average cost-effective. However, the low number of both vaccinated and unvaccinated severe TB cases leads to broad confidence intervals on vaccine efficacy, highlighting the difficulty associated with decision-making in low-prevalence settings.

Infection with HIV is characterized by very diverse disease-progression patterns across patients, associated with a wide variation in viral set-points. Progression is a multifactorial process, but an important role has been attributed to the HIV-specific T-cell response. To explore the conditions under which different set-points may be explained by differences in initial CD4 and CD8 T-cell responses and virus inoculum, we have formulated a model assuming that HIV-specific CD4 cells are both targets for infection and mediators of a monoclonal or polyclonal immune response. Clones differ in functional avidity for HIV epitopes. Importantly, in contrast to previous models, in this model we obtained coexistence of multiple clones at steady-state viral set-point, as seen in HIV infection. We found that, for certain parameter conditions, multiple steady states are possible: with few initial CD4 helper cells and high virus inoculum, no immune response is established and target-cell-limited infection follows, with associated high viral load; when CD4 clones are initially large and virus inoculum is low, infection can be controlled by several clones. The conditions for the dependence of viral set-point on initial inoculum and CD4 T-helper clone availability are investigated in terms of the effector mechanism of the clones involved.

A seasonal rise in tuberculosis (TB) notifications has been confirmed in several studies. Here, we examined one hypothesis for its cause: increased transmission of TB during wintertime due to crowding. Seasonality analysis was performed on actual and simulated notifications of clustered TB cases, which are considered to be representative of recent transmission, diagnosed from 1993 to 2004 in the Netherlands (n = 4,746). To test the hypothesis of winter crowding, notifications were simulated by adding patient delay and incubation period to an infection date randomly taken to be in winter in 80% of cases. The incubation periods were derived from frequency distributions for different TB disease localizations drawn from the literature. Seasonality analysis was performed using autocorrelation function plots and spectral analysis. Actual notifications showed strong seasonality in clustered TB and clustered extrapulmonary TB cases but not in clustered pulmonary TB cases. Analysis of simulated notifications revealed barely significant seasonality only in extrapulmonary TB cases. Our results suggest that increased transmission of TB during wintertime is unlikely to be the only cause of the seasonal peak in TB notifications. A factor closer to the notification date probably contributes to the seasonality observed in TB notifications.

Although we cannot rule out a mechanism of altered proliferation or death rate, the thymus plays an important role in the long-term recovery of naive T cells under IL-2 therapy.

BackgroundWhile the burden of community‐acquired pneumonia and invasive pneumococcal disease (IPD) is still considerable, there is little insight in the factors contributing to disease. Previous research on the lagged relationship between respiratory viruses and pneumococcal disease incidence is inconclusive, and studies correcting for temporal autocorrelation are lacking.ObjectivesTo investigate the temporal relation between influenza‐like illnesses (ILI) and IPD, correcting for temporal autocorrelation.MethodsWeekly counts of ILI were obtained from the Sentinel Practices of NIVEL Primary Care Database. IPD data were collected from the Dutch laboratory‐based surveillance system for bacterial meningitis from 2004 to 2014. We analysed the correlation between time series, pre‐whitening the dependent time series with the best‐fit seasonal autoregressive integrated moving average (SARIMA) model to the independent time series. We performed cross‐correlations between ILI and IPD incidences, and the (pre‐whitened) residuals, in the overall population and in the elderly.ResultsWe found significant cross‐correlations between ILI and IPD incidences peaking at lags ‐3 overall and at 1 week in the 65+ population. However, after pre‐whitening, no cross‐correlations were apparent in either population group.ConclusionOur study suggests that ILI occurrence does not seem to be the major driver of IPD incidence in The Netherlands.