The mechanism of CD4+ T-cell loss in infection with HIV is a hotly debated issue and has frequently been suggested to reflect impairment of thymic function resulting from viral pathology. However, a recent report in the European Journal of Immunology rules out this mechanism and provides the first direct evidence indicating that the thymus has limited influence on peripheral T-cell loss in HIV infection.

To assess the role of the thymus in peripheral T-cell homeostasis, Linqi Zhang and colleagues thymectomized juvenile rhesus macaques. Analysis of the peripheral T-cell pool for ten months following surgery indicated that thymectomized animals had a small but significant reduction in peripheral T-cell numbers compared with control animals that had sham surgery, with the fastest decline being in the CD4+ T-cell population. In the thymectomized animals, there was a small increase in the percentage of proliferating T cells, which the authors suggested might compensate for the loss of thymus-derived T cells. In addition, to follow the influence of thymectomy on the number of recent thymic emigrants in the periphery, the authors also measured T-cell receptor (TCR) excision circles (TRECs) — episomal DNA by-products present in cells that have undergone TCR rearrangement. As expected, TREC numbers declined in the thymectomized animals, whereas sham-operated macaques had stable TREC numbers. From analysis of the TREC decay rates in thymectomized animals, the authors were able to estimate the proportion of the total T-cell population that is produced by the thymus per day. So, although the thymus is crucial for the initial establishment of the T-cell repertoire, its ongoing contribution to the mature T-cell pool is small: only 0.2–0.3% of the peripheral T-cell pool migrated from the thymus each day, which is consistent with the relatively small effects seen in the periphery of thymectomized animals.

The authors next assessed how lack of thymic output affected the outcome of infection with simian immunodeficiency virus (SIV). Contrary to expectations, SIV infection of thymectomized animals did not result in higher viral loads or faster disease progression compared with SIV-infected control animals. Moreover, comparable levels of CD4+ T-cell loss were seen in both thymectomized and sham-operated SIV-infected animals. Comparison of CD4+ T-cell loss in thymectomized animals before and after SIV infection revealed that the fastest decay occurred after infection, indicating that most CD4+ T-cell loss in SIV infection is not explained by the loss of thymic output. A significant decline in TREC numbers was also seen following SIV infection in both thymectomized and sham-operated animals, although the rate of decline was greater in thymectomized animals. Given that the number of TRECs per cell is influenced by cell proliferation and cell death, the authors suggest that this increased rate of TREC decay is attributable to the higher rates of CD4+ T-cell proliferation in thymectomized animals and not to the lack of thymic output.

So, given that thymic output seems to have a limited role in maintaining peripheral T-cell numbers, SIV-mediated impairment of thymic function might not be an important contributing factor to T-cell depletion in SIV infection.