Abstract
An essential branch of the adaptive immune system is formed by T cells which are produced in the thymus. The absence of T cells can be detrimental to the host as is the case in acquired immuno-deficiency syndrome (AIDS). The goal of this thesis is to gain insights into the
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dynamics of different T-cell subsets in healthy as well as disturbed situations. This information is important not only in understanding how the immune system is regulated normally, but also in guiding therapeutic strategies when the immune system gets disturbed. By combining mathematical modeling with experimental data, this thesis demonstrates how the two can complement each other in quantifying the kinetics of T cells , and in resolving some of the discrepancies in previous kinetic estimates and in the mechanisms of T-cell maintenance in mice and men. In young adult mice, we estimate that naive CD4 and CD8 T cells have expected life spans of 48 and 91 days, while CD4 and CD8 memory T cells have expected life spans of 12 and 17 days, respectively. Our analyses show that throughout life, naive T cell production in mice almost exclusively occurs in the thymus, which implies that in the event of lymphopenia in mice, thymic output is central to successful immune reconstitution. In contrast, studies based on T-cell receptor excision circles (TRECs) have suggested that in humans T-cell proliferation plays a key role in naive T-cell maintenance during adult life. Our results therefore highlight an important qualitative difference in T-cell dynamics between mice and humans. Extrapolation of experimental results from mice to humans should hence be done with caution. Recent work using deuterium labeling from our group indicated that in human adults naive T cells are kinetically homogeneous and very long-lived. This is in contrast to the current consensus that recent thymic emigrants (RTEs) form a separate short-lived sub-population of naive T cells. In several studies described in this thesis, we find no evidence that RTEs in either mice or men form a kinetically separate sub-population of naive T cells. The typical decline in CD4+ T-cell numbers that is observed during HIV infection is accompanied by a shift in the kinetics of both naive and memory CD4 and CD8 T cells to faster turnover rates compared to healthy controls. Our analyses show that in HIV-infected individuals, naive CD4 and CD8 T cells have a 3.3-12 fold shorter expected lifespan, and CD4 and CD8 memory T cells a 2.8-3.1 fold shorter expected lifespan compared to healthy controls. The increased T-cell loss rates in HIV infection are accompanied by higher per capita production rates of both naive and memory T cells. In naive T cells , this increased turnover can explain our observation that longitudinal TREC dynamics after infection are biphasic. In this case, HIV triggers a massive recruitment of naive T cells into the effector/memory compartment where they are quickly lost. We also predict shortening of naive T cell telomeres after HIV infection contrary to previous findings that telomeres are normal in HIV patients. This discrepancy can be attributed to the effect of individual variations when extrapolating cross-sectional data to longitudinal dynamics. We show that changes in thymic output, and T-cell death and proliferation rates tend to affect average TREC contents and telomere lengths similarly. Especially when naive T-cell life spans are affected, as is the case in HIV infection, the observed TREC dilution can only be explained by increased proliferation rates. Reduced thymic output could however add to the observed decline of naive T cells. Indeed, our mouse model of HIV-independent chronic immune activation shows that chronic immune activation is sufficient to cause severe naive T cell depletion, while decreased thymic output aggravates the naive T-cell loss. This suggests that therapeutic strategies for HIV infection that are aimed at boosting thymic function may fail to reconstitute the CD4 T cell pool if immune activation is not simultaneously kept under control.
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