Abstract
Abstract Since Ag-stimulated naïve T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4+ Th1 cells, but also a profound and persistent reduction in the size of the peripheral naïve CD4+ T cell pool. We further showed that the resulting perturbation in T cell homeostasis is mechanistically associated with parasite-induced thymic atrophy and more specifically with a loss in the architectural integrity of the thymic epithelium. This structural degeneration is accompanied by impaired thymic selection as evidenced by decreased CD5 expression on the few recent thymic emigrants that reach the periphery. The resulting quantitative and qualitative deficiency in naïve CD4+ T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. Interestingly, the changes in thymic structure and function induced by toxoplasma closely resemble those associated with the thymic involution that occurs during aging suggesting a possible influence of infection-induced alterations in the thymus on immunologic senescence. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious diseases.
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