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. 2008 Sep 1;49(1):1-8.
doi: 10.1097/QAI.0b013e318184fb28.

The contribution of the thymus to the recovery of peripheral naive T-cell numbers during antiretroviral treatment for HIV infection

Ruy M Ribeiro  1 , Rob J de Boer
Affiliations

The contribution of the thymus to the recovery of peripheral naive T-cell numbers during antiretroviral treatment for HIV infection

Ruy M Ribeiro et al. J Acquir Immune Defic Syndr. .

Abstract

The quantitative contribution of the thymus to the maintenance of peripheral populations of naive T cells is poorly understood. Several new lines of evidence indicate that thymic activity continues into adulthood, albeit at lower levels than in early life, and that this is important for a range of lymphopenic disorders. A measure of thymic activity that is often used is the quantification of T-cell receptor excision circles (TRECs). It has been shown that TREC levels decline after infection with HIV-1 and that they recover to above normal levels after antiretroviral treatment. The reasons for the latter observation are unknown. Here we quantitatively explore different possible causes for supranormal levels of TREC per cell and show that the small total number of cells involved in reconstituting the TREC+ T-cell pool of HIV-1-infected patients suffices to explain the observation. Even the expected small thymic outputs into a strongly depleted naive T-cell peripheral pool lead to a slow transient of elevated levels of TREC per cell. The main biological lesson from our quantitative modeling approach is that middle-aged human thymi continue to produce naive T cells and that this production can be demonstrated by tracking the increase of total TREC numbers (rather than the TREC content).

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Figures

Figure 1
Figure 1
Change with age in (a) TREC total (/µl), (b) TREC content (per naïve T cell), and (c) naïve T cells in the CD4+ population. The ● and □ represent data from HIV-infected and uninfected subjects, respectively. The straight lines show the best regression through the data for uninfected (solid line) and infected (dashed) subjects. There are no significant differences between the slopes of the lines in any panel, but there is an increased TREC content in HIV-infected subjects, when corrected for age (p=0.016). Data from .
Figure 2
Figure 2
Comparison of TREC content in lymph nodes and periphery. Experimentally measured cjTREC per CD4+ T-cell for uninfected (white) and infected individuals (shaded bars) from . Expected cjTREC content for treated individuals (black bars), if treatment leads to re-establishment of the relative proportion of TREC content between lymph nodes and periphery, i.e., the ratio between the black bars is the same as between the white bars.
Figure 3
Figure 3
Steady states of the RTE model (see Appendix) as a function of the RTE recruitment rate f. We allow for homeostasis on RTE recruitment, f, and naïve T cell renewal, p, by dividing these rates by H=1+(N/h)2. Panel (a) shows the effect of RTE recruitment on the total number of naive T cells (R+N), on truly naive T cells (N) and RTEs (R), and on the total number of TRECs (T). Panel (b) shows that the TREC content per naïve T cell, C, goes down when the actual RTE recruitment, f/H, goes up. Parameters: c=16, h=12.5 cells, p=0.01 day−1, f=0.1, dN=0.001 day−1, dR=1/21 day−1, σ=1 cell day−1.
Figure 4
Figure 4
Supra-normal TREC content during naive T cell recovery induced by the thymus. We consider the following model for TREC+ naive T cells, N+, and total naive T cells, N: dN+dt=ασ−dNN+and dNdt=σ+(p−dN)N. Thus, C=N+/N is the TREC content per naive T cell. Considering a human adult, the thymic output, σ, should be small. We assumed a thymic production of σ = 0.032 cell/µl/day corresponding to a fractional output of less than 10−4 /day (taking a count of 400 CD4+ T cells per µl for a normal individual 11). The parameter α was set to 1/8 to represent the TREC content of RTE (e.g., cord blood cells) . Since naive T cells are long-lived we give them a half-life of two years by setting dN=0.001 day−1, and if naive T cell numbers ultimately approach a normal steady state of N=400 cells after the transient recovery phase, one can solve that p=0.00092 day−1. At the steady state the normal TREC content is C=0.01 /cell (see the horizontal line in Panel (a)). For simplicity we start with no TREC+ cells (i.e., N+(0)=0). The three lines correspond to three initial populations sizes: N=10 (solid line), N=50 (dashed line), N=200 (dash-dotted line).
Figure 5
Figure 5
TREC levels versus naïve T-cell numbers. (a) For treated infected individuals (●) with low naïve T cell counts (<150 cell/µl, indicated by the vertical dashed line) the TREC content is higher than for individuals with higher naïve T-cell numbers or for uninfected individuals (□); whereas (b) TREC total are similar for a wide range of naïve T-cell counts, including both infected (●) and uninfected individuals (□). In panel (c) we present box plots of the TREC content for three groups, infected individuals with less than 150 cell/µl (n=16); infected individuals with more than 150 cell/µl (n=19); and uninfected individuals (n=8) (Data from .)
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