MHC-Linked Syngeneic Developmental Preference in Thymic Lobes Colonized with Bone Marrow Cells: A Mathematical model

Reconstitution of the T-cell compartment after bone marrow transplantation depends on successful colonization of the thymus by bone-marrow-derived progenitor cells. Recent studies compared the development of syngeneic and allogeneic bone-marrow-derived cells in cocultures with lymphoid-depleted fetal thymus explants, leading to the discovery of MHC-linked syngeneic developmental preference (SDP) in the thymus. To determine the nature of cell interactions among the bone marrow and thymic elements that might underlie SDP, we analyzed this phenomenon by mathematical modeling. The results indicate that syngeneic mature T cells, responsible for inducing this preference, probably interfere both with the seeding of allogeneic bone-marrow-derived thymocyte progenitors in the thymic stroma and with their subsequent proliferation. In addition, the possibility of augmented death among the developing allogeneic thymocytes cannot be ruled out.     

T cell developmental defects in 'viable motheaten' mice deficient in SHP-1 protein-tyrosine phosphatase. Developmental defects are corrected in vitro in the presence of normal hematopoietic-origin stromal cells and in vivo by exogenous IL-7

Defects in the gene that encodes SHP-1 protein tyrosine phosphatase result in multiple hematopoietic abnormalities and generalized autoimmunity in viable motheaten (me(v)) mice. These mice also exhibit early thymic involution and abnormalities in T cell development. Here, we describe the use of fetal thymic organ culture (FTOC) and bone marrow adoptive transfer to study the effects of SHP-1 deficiency on thymocyte development. Chimeric FTOC established with normal bone marrow placed onto deoxyguanosine-treated fetal thymic lobes or onto scid fetal thymic lobes generated T cells. Bone marrow from SHP-1-deficient me(v)/ me(v) mice generated decreased numbers of T cells in chimeric FTOC established using deoxyguanosine-treated thymi but generated normal numbers in chimeric FTOC established using scid thymi. However, scid fetal thymi seeded with me(v)/ me(v) bone marrow also exhibited morphological abnormalities and contained elevated numbers of macrophages. Addition of IL-7 to me(v)/ me(v) bone marrow-seeded scid FTOC led to increased cell numbers, particularly of macrophages. Intrathymic injection of IL-7 partially restored the ability of progenitor cells in me(v)/ me(v) bone marrow to populate the thymus of adoptive recipients. We conclude that abnormal T cell development in me(v)/ me(v) mice may in part be due to defects in the ability of bone marrow-derived accessory cells to provide bioavailable IL-7 to developing thymocytes.     

Thymic export in aged sheep: a continuous role for the thymus throughout pre- and postnatal life

A diverse repertoire among peripheral T cells is established in early life by thymic export when the naive T cell pool is first formed. In contrast, during adult life the thymus has been thought to play only a minor role in T cell homeostasis. As individuals age there is an increasing proportion of peripheral T cells bearing a memory phenotype, as well as a corresponding decrease in the number of naive T cells. The change in the composition of the peripheral T cell pool with age is thought to occur as a result of reduced or completely curtailed thymic export following thymic involution at puberty together with the antigen-driven expansion of naive T cells in the periphery. We examined thymic export throughout life in fetal, neonatal and aged sheep. We found that the thymus in adult animals showed an efficiency of production and export on a per gram basis equivalent to that observed for much younger animals, and continued to export substantial numbers of T cells long after puberty. The data demonstrate that naive T cells constantly enter the peripheral T cell pool at the same rate throughout fetal, neonatal and adult life, and that one in every 50 T cells in the peripheral lymphoid tissues of aged sheep had emigrated from the thymus in the previous 24 h. The data suggest that restoration by the thymus of a normal peripheral T cell repertoire in chronic T cell-depleting conditions should be possible in adult patients, provided the thymus is not damaged by disease or therapy.     

Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution

Age-associated thymic involution results in a diminished capacity to regenerate T cell populations, although the magnitude of this effect is unknown. In this report, thymic function was studied in aged vs.young adult mice after lethal irradiation and administration of T cell-depleted bone marrow (BM) from young mice. Abnormalities observed in aged thymi (reduced thymocyte numbers, histologic abnormalities) were not reversed by administration of young BM via bone marrow transplantation (BMT), but agend thymi displayed a normal thymocyte subset distribution and appropriately deleted Mls-reactive T cells after BMT. Aged BMT recipients regenerated significantly reduced numbers of splenic T cells compared to young recipients and showed increased peripheral expansion of thymic emigrants since a higher proportion of BM-derived T cells expressed a memory phenotype in aged vs.young BMT recipients. Because peripheral expansion of thymic emigrants could substantially increase the number of thymic progeny present in the spleen, we sought to measure thymic T cell regenerative capacity after BMT in a setting devoid of peripheral expansion. To do this, TCR-transgenic (Tg⁺) T cell-depleted BM was administered to aged and young recipients lacking antigen specific for the Tg⁺ TCR. Aged recipients regenerated approximately 50 % of the TCR Tg⁺ cells regenerated in young BMT recipients, providing evidence that even very aged thymi retain the capacity to regenerate significant numbers of mature T cell progeny. Therefore, thymic function is reduced with aged but it is not lost, suggesting that therapeutic approaches to enhance thymic function may be successful even in very aged hosts.     

AGE-RELATED CHANGES OF THYMUS – MORPHOLOGICAL and FUNCTIONAL ASPECTS –

The thymus involutes progressively throughout life, beginning at around the sexual maturation. In long-lived BG3F₁ hybrid mice, the thymic capacity to induce T cell differentiation begins to decline earlier than the onset of thymic involution, although the magnitude of the decline is different by the subpopulation of T cells. Morphologically, the most active secretory structure seems to be limited exclusively to the neonatal thymus and certain structural changes, reflective of a decline in secretory function, can be detected early in life and they become more pronounced with age. Heterogeneity of thymic epithelial cells is suggested by the facts that age-related and radiation induced decline of immune activites are different in degree by subpopulation of T cells, and the concept is also supported from a morphological viewpoint. It is thus apparent that age-related thymic involution results in decrease of recruitment of fresh capable T cells and increase of old exhausted T cells, eventually bringing about T cell insufficiency in the aged individuals. Such an impaired immune function in the aged mice can be effectively restored by the combined grafting of young bone marrow and newborn thymus, and the thymus is apparently the most limiting factor in the aged. The biological significance of age-related thymic involution is also discussed.     

Age-related changes of thymus--morphological and functional aspects.

The thymus involutes progressively throughout life, beginning at around the sexual maturation. In long-lived BC3F1 hybrid mice, the thymic capacity to induce T cell differentiation begins to decline earlier than the onset of thymic involution, although the magnitude of the decline is different by the subpopulation of T cells. Morphologically, the most active secretory structure seems to be limited exclusively to the neonatal thymus and certain structural changes, reflective of a decline in secretory function, can be detected early in life and they become more pronounced with age. Heterogeneity of thymic epithelial cells is suggested by the facts that age-related and radiation induced decline of immune activities are different in degree by subpopulation of T cells, and the concept is also supported from a morphological viewpoint. It is thus apparent that age-related thymic involution results in decrease of recruitment of fresh capable T cells and increase of old exhausted T cells, eventually bringing about T cell insufficiency in the aged individuals. Such an impaired immune function in the aged mice can be effectively restored by the combined grafting of young bone marrow and newborn thymus, and the thymus is apparently the most limiting factor in the aged. The biological signficance of age-related thymic involution is also discussed.     

胸腺发育与衰老相关基因调控的研究进展

胸腺是人体内重要的中枢免疫器官,是T淋巴细胞成熟的场所.在骨髓中产生的淋巴造血祖细胞通过血液进入胸腺,与胸腺基质细胞相互作用,最终形成成熟的CD4+/CD8+T细胞,返回到血液中参与细胞免疫.现在已发现许多基因参与胸腺发育、衰老,如Foxn1、Hox、Wnt4等.这些基因在胸腺组织内形成一个网络,相互制约影响,调控着胸...     

Bone marrow-thymus axis in senescence

This presentation offers a brief review of the bone marrow-thymus axis in senescence, a putatitive model for thymocyte differentiation, and recent results of our work on the status of pre-thymic stem cells in aged mice. The data presented here provide further evidence for a thymus endocrine influence on the bone marrow stem cells, specifically lymphocyte precursors. It has been pstulated that the thymic hormones may act on lymphocyte precursors in the bone marrow and that the loss of thymic factors during senescence may be a contributing factor to the decreased cellular immune function. This study used Haar's in vitro model to investigate the bone marrow-thymus axis in aged mice. Erythroid-depleted bone-marrow cells from 3-month- and 24-month-old CBA (Thy 1.2) mice were placed in the upper half of a blind-well chamber with thymus supernatant in the lower half. Experimental cells were treated with thymus supernatant for 1 hr prior to migration. This study confirmed that pre-thymic stem cells in aged bone marrow are deficient in their ability to migrate to the thymus supernatant. It also revealed that treatment of the old bone marrow with thymus supernatant, made from neonatal thymus cultures, could dramatically improve the thymus migrating ability of the aged bone-marrow stem cells.     

The long and the short of telomeres in bone marrow recipient SCID patients

Telomeres are noncoding DNA regions at the end of the chromosomes that are crucial for genome stability. Since telomere length decreases with cell division, they can be used as a signature of cell proliferation history. T-cell reconstitution in severe combined immunodeficiency (SCID) subjects, recipients of T-cell-depleted, allogeneic-related bone marrow cells, is due to the development and maturation of donor T-cell precursors in the infant's vestigial thymus and to homeostatic proliferation of mature T cells in the peripheral organs. Since T-cell function, thymic output, and T-cell clonal diversity are maintained long term in these patients, we investigated whether donor T-cell engraftment resulted in increased telomere shortening. Our study of seven SCID patients, following successful bone marrow transplantation, demonstrates that the patients' peripheral T cells did not exhibit greater than normal telomere shortening.     

Transplantation of retrovirally transduced bone marrow prevents autoimmune disease in aged mice by peripheral tolerance mechanisms

Transplantation of bone marrow (BM) engineered to express self-antigen has been shown to protect 100% of young mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), with thymic clonal deletion as a tolerance mechanism. Here, we asked whether aged mice can also be tolerised following transplantation with self-antigen-engineered BM and whether castration-induced thymus regrowth can enhance this outcomes. Then, 50% of aged mice were protected from EAE regardless of castration-induced thymus regrowth. EAE-free and diseased mice demonstrated MOG-specific lymphocyte proliferation and antibody production regardless of castration-induced thymus regrowth, consistent with lack of intrathymic deletion of self-antigen-reactive T cells. Although low chimerism levels ( < 4%) were observed, EAE-free mice showed significantly higher chimerism levels in lymphocytes in peripheral lymphoid organs compared with thymus. CD4⁺CD25⁺ regulatory T cells were elevated in lymph nodes of EAE-free mice. We conclude that transplantation of self-antigen expressing BM protects 50% of aged mice and castration-induced thymic regrowth had no effect on outcomes. Peripheral tolerance mechanisms are implicated since protection is associated with higher chimerism levels in peripheral T and B lymphocytes and with elevated regulatory T cells.     

Transplantation of retrovirally transduced bone marrow prevents autoimmune disease in aged mice by peripheral tolerance mechanisms

Transplantation of bone marrow (BM) engineered to express self-antigen has been shown to protect 100% of young mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), with thymic clonal deletion as a tolerance mechanism. Here, we asked whether aged mice can also be tolerised following transplantation with self-antigen-engineered BM and whether castration-induced thymus regrowth can enhance this outcomes. Then, 50% of aged mice were protected from EAE regardless of castration-induced thymus regrowth. EAE-free and diseased mice demonstrated MOG-specific lymphocyte proliferation and antibody production regardless of castration-induced thymus regrowth, consistent with lack of intrathymic deletion of self-antigen-reactive T cells. Although low chimerism levels (?相似文献   

Prothymocyte seeding in the thymus

A major gap in our understanding of T lymphocyte development is the process of stem cell differentiation into T lymphocyte precursors. An important question is whether bone marrow-derived stem cells become committed to T lymphoid lineage within the bone marrow, or whether this occurs once cells have entered the microenvironment of the thymus. Attempts to identify a haemapoietic precursor of thymocytes in mice, a "prothymocyte", have involved cell transfer experiments involving isolated and selected populations of bone marrow stem cells, as well as transformed or continuous cell lines representing early stage in mouse T cell development. Current information on the properties of stem cells which can seed the thymus is reviewed in this paper, and the possibility that progenitor T cells may be identified by their expression of receptor(s) which localise them into the thymus is considered.     

Thymic T cell export is not influenced by the peripheral T cell pool

The peripheral T cell pool is maintained both by export of naive T cells from the thymus and by post-thymic expansion of activated/memory T cells. However, it is not known whether the thymus can alter its output following peripheral T cell depletion. Using intrathymic injection of fluorescein isothiocyanate to detect recent thymic emigrants (RTE), we directly tested whether the thymus is able to alter the number of RTE or the CD4:CD8 ratio of RTE emigrating to the periphery in response to in vivo depletion of total peripheral T cells or CD4 T cells, respectively. Depletion of peripheral T cells was achieved with anti-Thy-1 or anti-CD4, at doses that did not affect thymocyte numbers. Depletion of greater than 70% of peripheral T cells by treatment with anti-Thy-1 in vivo did not alter the number or cell cycle status of RTE trafficking to lymph nodes or spleen during the peripheral reconstitution phase (6, 9, 12 days). Similarly, depletion of the majority of CD4 T cells, which significantly reduced the peripheral CD4:CD8 T cell ratio, did not alter the total number or the proportion of CD4⁺ CD8^? RTE in peripheral lymphoid organs. These data clearly indicate that thymic output is not influenced by downstream alterations in peripheral T cell pool size or CD4:CD8 ratio. Rather we contend that thymic T cell export is internally regulated by as yet undefined mechanisms.     

Stress-induced alterations in the programmed natural cycles of post-natal lymphoid organ development in C57BL/6 mice: Evidence for a regulatory feedback relationship between bone marrow and thymus

This study investigated some effects of weaning and immobilization stress in C57BL/6 mice aged 22-68 days, i.e., over a period including activation of the hypothalamus-pituitary-adrenal (HPA) axis and puberty. Specifically, the study evaluated the evolution, over the referred age interval, of a set of variables (body, thymus, spleen and axillary lymph nodes weights, the proportion of lymphoid cells in the bone marrow, the relative chemoattraction capacity of thymic supernatants for lymphoid cells and the migratory capacity of bone marrow lymphoid cells) in either weaned mice or weaned mice subjected to immobilization stress, compared to "non-stressed" unweaned mice. Cyclic patterns, observed for most variables in unweaned mice, were especially pronounced in two cases: the relative migratory capacity of bone marrow lymphoid cells collected at different ages towards neonatal thymic supernatant, and the relative chemoattraction capacity of thymic supernatants of different ages as tested against a sample of bone marrow lymphoid cells from mice aged 35 days. Weaning stress tended to intensify the involution stages of the cycles in thymus, spleen and lymph node weight, but increased the relative proportion of lymphoid cells in the bone marrow cell population. Both types of exogenous stress tended to affect cycle phase, i.e., cycle peaks and troughs were shifted in time. Correlations were observed between patterns seen in the thymus and bone marrow, suggesting the existence of an autoregulatory feedback loop governing pre-T cell migration and bone marrow/thymus homeostasis. These results also suggest that exogenous stress acts as a non-programmed regulator, modulating the naturally programmed cyclic patterns.     

T cell receptor excision circle assessment of thymopoiesis in aging mice

Signal joint T cell receptor delta (TCRD) excision circles (TRECs) are episomal DNA circles generated by the DNA recombination process that is used by T lymphocytes to produce antigen-specific alpha/beta T cell receptors. Measurement of TRECs in thymocytes and peripheral blood T cells has been used to study thymus output in chickens and humans. We have developed a real-time quantitative-PCR assay for the specific detection and quantification of mouse TCRD episomal DNA circles excised from the TCRA locus during TCRA gene rearrangement (mTRECs). We found that the mouse TCRD TRECs detected with this assay were predominantly in na?ve phenotype CD4(+) and CD8(+) T cells. In a series of aged mice (range 6-90-week-old) we determined the absolute number of thymocytes and the number of molecules of mTRECs/100,000 thymocytes. We found that the absolute number of thymocytes dramatically decreased with age (P<0.05) and that molecules of mTREC/100,000 thymocytes also declined with mouse age (P<0.05). Splenocytes were isolated from aging mice and the frequency of na?ve phenotype CD4 and CD8 cells determined. There was a significant drop in both CD4 and CD8 na?ve peripheral T cells in the aged mice over time. mTREC analysis in purified CD4(+) and CD8(+) splenocytes demonstrated a constant level of mTRECs in the CD4 compartment until age 90 weeks, while the mTRECs in the CD8 compartment fell with age (P<0.05). By combining the mouse TREC assay with T cell phenotypic analysis, we demonstrated that IL-7 administration to young mice induced both increased thymopoiesis and peripheral T cell proliferation. In contrast, IL-7 treatment of aged mice did not augment thymopoiesis, nor induce expansion of splenic T cells. Thus, thymus output continues throughout murine adult life, and the thymic atrophy of aging in mice is not reversed by administration of IL-7.     

T-cell tolerance.

Despite the acceptance of principles such as clonal deletion in the thymus and peripheral clonal anergy, several new issues have arisen in the study of T-cell tolerance. For example, in the case of thymic tolerance, it is now clear that several distinct components of the thymus, including various subsets of thymic epithelial cells, can all make contributions to the deletion of autoreactive T cells. In the case of peripheral T-cell tolerance, the induction of anergy now has been complicated by the possibility that bone marrow derived antigen presenting cells may, under certain conditions, be tolerogenic rather than stimulatory.     

Immunological aspects of aging: early changes in thymic activity

Age related changes in immune function are preceded by changes in thymic function. One index of thymic function is the ability of the thymus to induce the differentiation of bone marrow pre-T cells into active T cells. Movement of precursors of PHA-responsive T cells into the thymus ceases prior to adolescence in long-lived, autoimmune disease resistant mice as determined by studies utilizing chromosome markers in parabiotic mice. The cause for this age-dependent, cell traffic phenomenon is not known, but it would appear that an extrathymic regulatory mechanism may be operating, since these precursor T cells have the capacity to migrate into the thymus, and even a grafted, involuting thymus is capable of accepting precursor T cells, under extraordinary conditions. Results indicate that shortly after adolescence, immature T cell precursors of PHA-responsive cells in the thymus, and perhaps the periphery, are the sole source of PHA-responsive T cells. T cell migration and maturation is discussed in relation to thymic hormones and the thymic-neuroendocrine regulatory axis.     

Clonal elimination of self reactive V beta 6+ T cells induced by H-2 products expressed on thymic radio-resistant components.

The role of thymic radio-resistant cells on clonal elimination of V beta 6+ T cells that are reactive to minor lymphocyte stimulatory (Mls)-1a plus I-E antigens has been investigated. Previous studies with allogeneic bone marrow chimeras revealed that radio-sensitive I-E+ cells derived from donor bone marrow in the thymus play a major role in the clonal elimination of V beta 6+ T cells. However, we could show that not only the thymic bone marrow derived components but also the radio-resistant ones (presumably thymic epithelial cells) might be involved in induction of clonal elimination of the self-reactive T cells. The proportion of V beta 6+ T cells present varied with the H-2 haplotype of the thymus and the cell types presenting Mls-1a products, which might be attributable to differences in the affinity of the H-2 products to T cell antigen receptors and differences in the amount of tolerogens expressed on the stromal cells.     

Insights into thymic aging and regeneration

Summary: The deterioration of the immune system with progressive aging is believed to contribute to morbidity and mortality in elderly humans due to the increased incidence of infection, autoimmunity, and cancer. Dysregulation of T‐cell function is thought to play a critical part in these processes. One of the consequences of an aging immune system is the process termed thymic involution, where the thymus undergoes a progressive reduction in size due to profound changes in its anatomy associated with loss of thymic epithelial cells and a decrease in thymopoiesis. This decline in the output of newly developed T cells results in diminished numbers of circulating naïve T cells and impaired cell‐mediated immunity. A number of theories have been forwarded to explain this ‘thymic menopause’ including the possible loss of thymic progenitors or epithelial cells, a diminished capacity to rearrange T‐cell receptor genes and alterations in the production of growth factors and hormones. Although to date no interventions fully restore thymic function in the aging host, systemic administration of various cytokines and hormones or bone marrow transplantation have resulted in increased thymic activity and T‐cell output with age. In this review, we shall examine the current literature on thymic involution and discuss several interventional strategies currently being explored to restore thymic function in elderly subjects.