The Role of the Thymus and Recent Thymic Migrants in the Maintenance of the Adult Peripheral Lymphocyte Pool

Abstract

The thymus is essential for the initial seeding of T cells to the periphery, but its role in maintaining the adult T cell pool remains poorly defined. We investigated whether changes to the rate of T cell export could form part of the mechanism(s) controlling the homeostatic regulation of the size and composition of the peripheral T cell pool. Using neonatal thymi grafted under the kidney capsule, we found that irrespective of whether the pool was oversupplied (by thymic grafts) or undersupplied (due to neonatal thymectomy), the thymic export rate was constant from both the host and graft thymus, and the periphery remained constant in size. Recent thymic emigrants (RTE) were also tracked to determine the extent of their acceptance into the T cell pool of a normal mouse. As a population, RTE are phenotypically mature, but were distinct from resident T cells in the periphery, being released in a CD4/CD8 ratio approximately twice that of established peripheral T cells. This export ratio is similar to that of T cells in the mature thymic compartment, but soon after entry into the periphery, the ratio falls, indicating separate thymic and peripheral regulation of the CD4/CD8 ratio. RTE may also be preferentially incorporated into the periphery, causing displacement of resident T cells, thus maintaining the size of the peripheral pool. Although not vital for the maintenance of a functional T cell pool, the acceptance of RTE in a “full” peripheral pool would ensure that the T cell receptor repertoire is kept diverse and that the T cell population encompasses a broad range of naive as well as memory T cells.

Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

“…Our experiments did not address possible effects of natural regulatory T cells on the size of the naive CD4 T cell pool which is obviously dependent on thymic output (7,31). For CD8 T cells, it was suggested that the pools of naive and activated/memory cells are independently regulated (8).…”

“…In the mouse, export of ϳ10 6 T cells/day from the thymus to the periphery (5) requires the loss of similar numbers of peripheral resident T cells. Recent observations suggest that this peripheral T cell loss is mostly due to the replacement of naive resident T cells by recent thymic emigrants (6,7). Furthermore, studies using TCR-transgenic animal models conclude that the naive and the activated/memory CD8 T cell pools are independently regulated (8,9).…”

Differential Survival of Naive CD4 and CD8 T Cells

“…The ratio of CD4 to CD8 T cells in normal mice is controlled homeostatically, but less is known about its conservation in the absence of thymic output. Recent thymic emigrants contain about 4 times more CD4 than CD8 T cells, and normalization of the ratio in secondary lymphoid organs implies that some CD4 T cells are deleted, whereas, in contrast, some CD8 T cells are proliferating (37). The question of how homeostasis is achieved after profound T cell depletion and in the absence of thymic output has important consequences for therapy in humans.…”

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

“…These experiments showed that the thymic settling progenitors that normally settle the thymus are only able to give rise to a single round of thymocyte differentiation. These experiments led to the supposition that long-term thymocyte differentiation requires an on-going migration of donor progenitors from the BM to the thymus, with new BM precursors replacing resident thymocytes [32][33][34][35].…”