Gated Importation of Prothymocytes by Adult Mouse Thymus Is Coordinated with Their Periodic Mobilization from Bone Marrow

Abstract

The wavelike pattern of fetal T cell neogenesis is largely determined by the intermittent generation and exportation of waves of prothymocytes by the hemopoietic tissues in coordination with their gated importation by the thymus. Having previously shown that the importation of prothymocytes by the adult mouse thymus is also gated and that thymocytopoiesis proceeds in discrete (albeit overlapping) waves, we now demonstrate that prothymocytes are periodically exported in saturating numbers from the adult mouse bone marrow. Experiments in normal, radioablated, and parabiotic mice document the cyclical accumulation (3–5 wk) of prothymocytes in both the steady state and regenerating bone marrow, followed by their release into the blood ∼1 wk before intrathymic gate opening. The results also show that circulating donor-origin thymocyte precursors can transiently (∼1 wk) establish high level chimerism in the bone marrow after the mobilization of endogenous prothymocytes, presumably by occupying vacated microenvironmental niches. Hence, by analogy with the fetal state, we posit the existence of a feedback loop whereby diffusible chemokines of thymic origin regulate the production and/or release of bone marrow prothymocytes during each period of thymic receptivity. Because each resulting wave of thymocytopoiesis is accompanied by a wave of intrathymic dendritic cell formation, these coordinated events may help to optimize thymocyte selection as well as production.

Early Growth Response Gene 1 Provides Negative Feedback to Inhibit Entry of Progenitor Cells into the Thymus

“…Hence, a wave of progenitors is released from the BM about 1 wk before the thymus becomes responsive to progenitor entry (2). This suggests that the thymus may be able to feed back both to progenitors in the BM, and to the thymic stroma at the site of progenitor entry.…”

“…The release of progenitors into the blood from the BM and the entry of these progenitors into the thymus is a coordinated process in which the thymus goes through refractory and responsive periods (2,3). Hence, a wave of progenitors is released from the BM about 1 wk before the thymus becomes responsive to progenitor entry (2).…”

The role of apoptosis in the development and function of T lymphocytes

“…In adults, thymocyte development begins with the migration of multipotent precursors from the bone marrow into the thymus. These precursor cells periodically enter the thymus through postcapillary venules in the cortex region close to the corticomedullary junction [126,127]. After entering the thymus, the precursor cells differentiate into DN1 cells (CD44 + CD25 -).…”

Mechanisms of thymus organogenesis and morphogenesis

“…This precisely controlled cyclic mechanism operates during both avian and mouse organogenesis and is controlled by the thymic stroma (Ritter, 1978;Jotereau and Le Douarin, 1982;Coltey et al, 1987). This property of periodic permissiveness for LPC entry is actually continued in the postnatal thymus (Foss et al, 2001;Donskoy et al, 2003;Goldschneider, 2006), although it is not clear whether the mechanisms controlling this process are precisely the same in the fetal and postnatal thymus.…”