Microenvironmental regulation of T cell development in the thymus

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.

Section: Discussionmentioning

confidence: 99%

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

Donskoy

Foss

Goldschneider

2003

“…Throughout the development of T cells there are multiple chances for a cell to undergo apoptosis. One of the first opportunities occurs in the thymus, where a developing cell can undergo death by neglect if it lacks a TCR with sufficient affinity for MHC class I complexed with the appropriate self ligand or death through negative selection if the TCR/MHC interaction is too strong (1,2). Throughout the double-positive (CD8 ϩ CD4 ϩ ) stages these thymocytes are extremely sensitive to agents such as dexamethasone and irradiation, which induce apoptosis through production of reactive oxygen species and loss of mitochondrial function (3,4).…”

Section: Cd8mentioning

confidence: 99%

Differential Sensitivity of Naive and Memory CD8+ T Cells to Apoptosis in Vivo

Grayson

Harrington

Lanier

et al. 2002

192

165

Apoptosis is a critical regulator of homeostasis in the immune system. In this study we demonstrate that memory CD8+ T cells are more resistant to apoptosis than naive cells. After whole body irradiation of mice, both naive and memory CD8+ T cells decreased in number, but the reduction in the number of naive cells was 8-fold greater than that in memory CD8+ T cells. In addition to examining radiation-induced apoptosis, we analyzed the expansion and contraction of naive and memory CD8+ T cells in vivo following exposure to Ag. We found that memory CD8+ T cells not only responded more quickly than naive cells after viral infection, but that secondary effector cells generated from memory cells underwent much less contraction compared with primary effectors generated from naive cells (3- to 5-fold vs 10- to 20-fold decrease). Increased numbers of secondary memory cells were observed in both lymphoid and non-lymphoid tissues. When naive and memory cells were transferred into the same animal, secondary effectors underwent less contraction than primary effector cells. These experiments analyzing apoptosis of primary and secondary effectors in the same animal show unequivocally that decreased downsizing of the secondary response reflects an intrinsic property of the memory T cells and is not simply due to environmental effects. These findings have implications for designing prime/boost vaccine strategies and also for optimizing immunotherapeutic regimens for treatment of chronic infections.

“…Moreover, the developmental process continues after birth because T cell development implies the entrance of bone marrow cell precursors into the thymus that differentiate in a mature and compartmented thymic stroma. The process involves cell movement through different thymic compartments as well as processes of attachment and detachment while developmental and cell fate signals are given to the developing thymocytes by the thymic stromal cells (16,17).…”

mentioning

confidence: 99%

Thymic Alterations in EphA4-Deficient Mice

Múñoz

Alfaro

García‐Ceca

et al. 2006

In the present work, we have demonstrated in vivo an altered maturation of the thymic epithelium that results in defective T cell development which increases with age, in the thymus of Eph A4-deficient mice. The deficient thymi are hypocellular and show decreased proportions of double-positive (CD4+CD8+) cells which reach minimal numbers in 4-wk-old thymi. The EphA4 −/− phenotype correlates with an early block of T cell precursor differentiation that results in accumulation of CD44−CD25+ triple-negative cells and, sometimes, of CD44+CD25− triple-negative thymocytes as well as with increased numbers of apoptotic cells and an important reduction in the numbers of cycling thymocytes. Various approaches support a key role of the thymic epithelial cells in the observed phenotype. Thymic cytoarchitecture undergoes profound changes earlier than those found in the thymocyte maturation. Thymic cortex is extremely reduced and consists of densely packed thymic epithelial cells. Presumably the lack of forward Eph A4 signaling in the Eph A4 −/− epithelial cells affects their development and finally results in altered T cell development.