Dynamics of Recent Thymic Emigrants in Young Adult Mice (original) (raw)
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Post-thymic maturation: young T cells assert their individuality
Nature Reviews Immunology, 2011
T cell maturation was once thought to occur entirely within the thymus. Now, evidence is mounting that the youngest peripheral T cells in both mice and humans comprise a distinct population from their more mature, yet still naive, counterparts. These cells, termed recent thymic emigrants (RTEs), undergo a process of post-thymic maturation that can be monitored at the levels of cell phenotype and immune function. Understanding this final maturation step in the process of generating useful and safe T cells is of clinical relevance, given that RTEs are over-represented in neonates and in adults recovering from lymphopenia. Post-thymic maturation may function to ensure T cell fitness and self tolerance.
The Journal of Immunology
Studies of the functional properties and developmental potentials of immediate post-thymic cells have been hampered by the lack of reliable markers with which to distinguish recent thymic emigrants (RTE) from the bulk of peripheral T cells. In the present study, the intrathymic FITC-labeling technique was used in concert with three-color flow-cytometric analysis to identify, phenotypically characterize, and study the short term fate of RTE in normal rats. The results indicated that between 3 and 4% of total T cells in lymph node and spleen of 5- to 8-wk-old rats had been released from the thymus within the preceding 24 h. Unlike the bulk of the peripheral T cells, which had a Thy1-, CD45RC+, and/or RT6+ phenotype, these RTE were Thy1+, CD45RC-, and RT6-. Furthermore, two discrete subsets of RTE were defined: a major subset (approximately 95%) of CD4+ or 8+ (single positive), TCR-alpha beta hi T cells that resembled medullary thymocytes; and a minor subset (approximately 5%) of CD4+ ...
We developed a novel experimental strategy to study T cell regeneration after bone marrow transplantation. We assessed the fraction of competent precursors required to repopulate the thymus and quantified the relationship between the size of the different T cell compartments during T cell maturation in the thymus. The contribution of the thymus to the establishment and maintenance of the peripheral T cell pools was also quantified. We found that the degree of thymus restoration is determined by the availability of competent precursors and that the number of double-positive thymus cells is not under homeostatic control. In contrast, the sizes of the peripheral CD4 and CD8 T cell pools are largely independent of the number of precursors and of the number of thymus cells. Peripheral "homeostatic" proliferation and increased export and/or survival of recent thymus emigrants compensate for reduced T cell production in the thymus. In spite of these reparatory processes, mice with a reduced number of mature T cells in the thymus have an increased probability of peripheral T cell deficiency, mainly in the naive compartment.
Immunology and Cell Biology, 2003
Analysing T-cell receptor excision circle numbers in healthy individuals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for individuals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older individuals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for individuals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.
A central role for thymic emigrants in peripheral T cell homeostasis
Proceedings of the National Academy of Sciences, 1999
After initial seeding by thymic emigrants, homeostatic regulation of the T cell pool has been thought to occur entirely within the periphery. Here we report that the degree of thymic emigration directly affects the number and the CD4͞CD8 ratio of peripheral T cells. We demonstrate that the increase in T cell pool size caused by the engraftment of 2, 6, or 9 thymic lobes correlates almost exactly with the number of emigrants exported from those grafts in the previous 3 weeks, regardless of how long the graft has been in place. The extent of the increase supports the concept of a 3-week period after thymic export in which emigrant T cells are exempt from peripheral T cell homeostasis. This apparent exclusion of recent thymic emigrants from the niche-based regulation of peripheral T cell numbers ensures repertoire turnover throughout adult life and provides the basis of a direct and previously unrecognized role for the thymus in the regulation of peripheral T cell homeostasis.
Recent thymic origin, differentiation, and turnover of regulatory T cells
Journal of Leukocyte Biology, 2008
Regulatory CD4 ؉ T cells (T reg) are essential to maintain self-tolerance. Release of natural T reg from the thymus is believed to commence soon after birth, but it is unclear how many are produced by "conversion" in the periphery, whether numbers are maintained after puberty by general homeostatic mechanisms that regulate lymphocyte numbers, or whether significant numbers are produced by the involuted thymus. To address the origin of T reg in normal adult rats, we focused on recent thymus emigrants (RTE). Approximately 30% of CD4 ؉ CD25 ؉ forkhead box p3 (Foxp3) ؉ T reg expressed markers associated with RTE. Following thymectomy, numbers of cells expressing these markers fell by 80% within 30 days. Furthermore, although only ϳ5% of CD4 ؉ single-positive thymocytes expressed Foxp3, within 24 h after intrathymic injection of FITC, more than 30% of the labeled CD4 ؉ RTE in the periphery were Foxp3 ؉ , suggesting that some RTE may acquire Foxp3 in the periphery. Thus, some RTE may acquire Foxp3 rapidly after emigration from the thymus. T reg are dividing rapidly with apparent half-lives of ϳ18 days and ϳ7 days for the CD4 ؉ CD25 ؉ Foxp3 ؉ and CD4 ؉ CD25-Foxp3 ؉ subsets, respectively. The apparently slower turnover of CD4 ؉ CD25 ؉ Foxp3 ؉ cells is a result of CD4 ؉ CD25 ؉ Foxp3 ؉ 3 CD4 ؉ CD25-Foxp3 ؉ conversion with no loss of regulatory function. Taken together, the data suggest that T reg in adults are relatively short-lived and that their numbers are maintained by rapid cell division and continuous replenishment from the thymus.
Critical influence of the thymus on peripheral T cell homeostasis
Immunity, inflammation and disease, 2016
A tight balance between regulatory CD4(+)Foxp3(+) (Treg) and conventional CD4(+)Foxp3(-) (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self-tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment. We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Additionally, lymphoid cells from young and aged B6 mice were intravenously transferred to B6.RAG2(-/-) mice. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days by flow cytometry. Thymectomi...
Proceedings of the National Academy of Sciences, 2008
In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool.
Age‐related changes in the occurrence and characteristics of thymic CD4+ CD25+ T cells in mice
2007
Natural regulatory CD4 + CD25 + T cells play an important role in preventing autoimmunity by maintaining self-tolerance. They express CD25 constitutively and are produced in the thymus as a functionally mature T-cell population. Changes in the potential of these cells to regulate the activity of conventional effector lymphocytes may contribute to an increased susceptibility to infection, cancer and age-associated autoimmune diseases. In this study we demonstrated that the thymi of aged mice are populated by a higher percentage of CD4 + CD25 + thymocytes than in young animals. The expression of several surface markers (CD69, CD5, CD28, CTLA-4, CD122, FOXP3), usually used to characterize the phenotype of CD4 + CD25 + T regulatory cells, was compared between young and aged mice. We also examined the ability of sorted thymusderiving regulatory T cells of young and aged BALB/c mice to inhibit the proliferation of lymph node lymphocytes activated in vitro. Natural regulatory T cells isolated from the thymi of young mice suppress the proliferation of responder lymph node cells. We demonstrated that thymus-deriving CD4 + CD25 + T cells of old mice maintain their potential to suppress the proliferation of activated responder lymphocytes of young mice. However, their potential to inhibit the proliferation of old responder T cells is abrogated. Differences in the occurrence and activity of CD4 + CD25 + thymocytes between young and old animals are discussed in relation to the expression of these surface markers.