Browsing by Subject "Thymus Gland"

Now showing 1 - 8 of 8
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    A role of the CTCF binding site at enhancer Eα in the dynamic chromatin organization of the Tcra-Tcrd locus.
    (Nucleic acids research, 2020-09) Zhao, Hao; Li, Zhaoqiang; Zhu, Yongchang; Bian, Shasha; Zhang, Yan; Qin, Litao; Naik, Abani Kanta; He, Jiangtu; Zhang, Zhenhai; Krangel, Michael S; Hao, Bingtao
    The regulation of T cell receptor Tcra gene rearrangement has been extensively studied. The enhancer Eα plays an essential role in Tcra rearrangement by establishing a recombination centre in the Jα array and a chromatin hub for interactions between Vα and Jα genes. But the mechanism of the Eα and its downstream CTCF binding site (here named EACBE) in dynamic chromatin regulation is unknown. The Hi-C data showed that the EACBE is located at the sub-TAD boundary which separates the Tcra-Tcrd locus and the downstream region including the Dad1 gene. The EACBE is required for long-distance regulation of the Eα on the proximal Vα genes, and its deletion impaired the Tcra rearrangement. We also noticed that the EACBE and Eα regulate the genes in the downstream sub-TAD via asymmetric chromatin extrusion. This study provides a new insight into the role of CTCF binding sites at TAD boundaries in gene regulation.
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    Health Consequences of Thymus Removal in Adults.
    (The New England journal of medicine, 2023-11) Morena, Jonathan; Duke Myasthenia Gravis Physicians
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    Histopathologic assessment of cultured human thymus.
    (PloS one, 2020-01) Hale, Laura P; Neff, Jadee; Cheatham, Lynn; Cardona, Diana; Markert, M Louise; Kurtzberg, Joanne
    The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival. This study was designed to assess the histopathologic changes that occur in postnatal human thymus slices when cultured according to protocols used for transplanted tissues. Results showed that as thymic organ cultures progressed from days 0 through 21, slices developed increasing amounts of necrosis, increasing condensation of thymic epithelium, and decreasing numbers of residual T cells. The architecture of the thymic epithelial network remained generally well-preserved throughout the 21 days of culture, with focal expression of cytokeratin 14, a putative biomarker of thymic epithelial cells with long-term organ-repopulating potential. All organ slices derived from the same donor thymus closely resembled one another, with minor differences in size, shape, and relative content of cortex versus medulla. Similarly, slices derived from different donors showed similar histopathologic characteristics when examined at the same culture time point. Taken together, these results demonstrate that diagnostic criteria based on structural features of the tissue identifiable via hematoxylin and eosin staining and cytokeratin immunohistochemistry can be used to evaluate the quality of slices transplanted into patients with congenital athymia.
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    HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53.
    (Genes Dev, 2007-04-01) Sasaki, Toru; Gan, Eugene C; Wakeham, Andrew; Kornbluth, Sally; Mak, Tak W; Okada, Hitoshi
    In response to DNA damage, p53 undergoes post-translational modifications (including acetylation) that are critical for its transcriptional activity. However, the mechanism by which p53 acetylation is regulated is still unclear. Here, we describe an essential role for HLA-B-associated transcript 3 (Bat3)/Scythe in controlling the acetylation of p53 required for DNA damage responses. Depletion of Bat3 from human and mouse cells markedly impairs p53-mediated transactivation of its target genes Puma and p21. Although DNA damage-induced phosphorylation, stabilization, and nuclear accumulation of p53 are not significantly affected by Bat3 depletion, p53 acetylation is almost completely abolished. Bat3 forms a complex with p300, and an increased amount of Bat3 enhances the recruitment of p53 to p300 and facilitates subsequent p53 acetylation. In contrast, Bat3-depleted cells show reduced p53-p300 complex formation and decreased p53 acetylation. Furthermore, consistent with our in vitro findings, thymocytes from Bat3-deficient mice exhibit reduced induction of puma and p21, and are resistant to DNA damage-induced apoptosis in vivo. Our data indicate that Bat3 is a novel and essential regulator of p53-mediated responses to genotoxic stress, and that Bat3 controls DNA damage-induced acetylation of p53.
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    Intercellular Protein Transfer from Thymocytes to Thymic Epithelial Cells.
    (PLoS One, 2016) Wang, Hong-Xia; Qiu, Yu-Rong; Zhong, Xiao-Ping
    Promiscuous expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is crucial for negative selection of self-reactive T cells to establish central tolerance. Intercellular transfer of self-peptide-MHC complexes from mTECs to thymic dendritic cells (DCs) allows DCs to acquire TRAs, which in turn contributes to negative selection and regulatory T cell generation. However, mTECs are unlikely to express all TRAs, such as immunoglobulins generated only in B cells after somatic recombination, hyper-mutation, or class-switches. We report here that both mTECs and cortical TECs can efficiently acquire not only cell surface but also intracellular proteins from thymocytes. This reveals a previously unappreciated intercellular sharing of molecules from thymocytes to TECs, which may broaden the TRA inventory in mTECs for establishing a full spectrum of central tolerance.
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    T cell-depleted cultured pediatric thymus tissue as a model for some aspects of human age-related thymus involution.
    (GeroScience, 2021-06) Hale, Laura P; Cheatham, Lynn; Macintyre, Andrew N; LaFleur, Bonnie; Sanders, Brittany; Troy, Jesse; Kurtzberg, Joanne; Sempowski, Gregory D
    Human age-related thymus involution is characterized by loss of developing thymocytes and the thymic epithelial network that supports them, with replacement by adipose tissue. The mechanisms that drive these changes are difficult to study in vivo due to constant trafficking to and from the thymus. We hypothesized that the loss of thymocytes that occurs during human thymic organ cultures could model some aspects of thymus involution and begin to identify mechanisms that drive age-related changes in the thymic microenvironment. Potential mechanistically important candidate molecules were initially identified by screening conditioned media from human thymus organ cultures using antibody microarrays. These candidates were further validated using cultured tissue extracts and conditioned media. Results were compared with gene expression studies from a panel of well-characterized (non-cultured) human thymus tissues from human donors aged 5 days to 78 years. L-selectin released into conditioned media was identified as a biomarker for the content of viable thymocytes within the cultured thymus. Levels of the chemokines CCL21 and CXCL12, likely produced by surviving thymic epithelial cells, increased markedly in conditioned media as thymocytes were lost during culture. Native non-cultured thymus from adults older than 18 years also showed a strong trend toward increased CCL21 expression, in conjunction with significant decreases in thymocyte-related mRNAs compared with thymus from subjects younger than 18 years. Together, these findings demonstrate that use of postnatal human thymus organ cultures can model some aspects of human age-related thymic involution.
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    The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.
    (J Clin Invest, 2010-01) Na, Il-Kang; Lu, Sydney X; Yim, Nury L; Goldberg, Gabrielle L; Tsai, Jennifer; Rao, Uttam; Smith, Odette M; King, Christopher G; Suh, David; Hirschhorn-Cymerman, Daniel; Palomba, Lia; Penack, Olaf; Holland, Amanda M; Jenq, Robert R; Ghosh, Arnab; Tran, Hien; Merghoub, Taha; Liu, Chen; Sempowski, Gregory D; Ventevogel, Melissa; Beauchemin, Nicole; van den Brink, Marcel RM
    Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
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    Thymic requirement for cyclical idiotypic and reciprocal anti-idiotypic immune responses to a T-independent antigen.
    (J Exp Med, 1980-02-01) Kelsoe, G; Isaak, D; Cerny, J
    The role of the thymus in the cyclical appearance of the dominant idiotype of the myeloma protein secreted by the TEPC-15 plasmacytoma (T-15)-bearing plaque-forming cells (PFC) and anti-idiotypic cells (i.e., cells with receptors for T-15) in the spleen during a primary response to the phosphorylcholine determinant of Streptococcus pneumoniae, strain R36a (Pn) was studied using normal mice, thymus-deficient nude mice, and thymus gland-grafted nude mice (TG-nude). The nude mice and their phenotypically normal littermates (LM) were backcrossed on the BALB/c genetic background. The kinetics of the anti-Pn PFC response of BALB/c inbred mice, littermates of nude mice, and TG-nude mice were essentially the same. There was an initial peak on day 5-6 followed by a decline to near background, and then a second peak on day 12. In nude mice, the first peak of anti-Pn PFC (day 5) was comparable in magnitude to that of mice with an intact thymus; however, there was no second peak. In contrast to the cellular response measured at the level of PFC, the serum antibody response to Pn (assayed by passive hemagglutination of sheep erythrocytes coated with Pn polysaccharide) was comparable in all groups of mice and did not show a measurable oscillation. The anti-idiotypic cellular activity was determined by the ability of spleen cells to bind radiolabeled (125I) TEPC-15 myeloma protein (IgA, kappa) which carries an idiotypic determinant indistinguishable from that of most anti-phosphorylcholine antibodies in BALB/c mice. Binding of radiolabeled McPC-603 (IgA, kappa) and MOPC-315 (IgA, lambda 2) myeloma proteins (which lack the T-15 idiotypic determinant) served as controls. The changes in T-15 binding by splenic lymphocytes following the Pn immunization differed between normal and athymic mice. BALB/c, LM, and TG-nude mice showed a biphasic pattern with peaks at days 3--4 and 10--11 that was nearly reciprocal to the PFC curve. On the other hand, T-15 binding in nude mice either declined and remained depressed or was not affected by the ongoing anti-Pn response. These observations demonstrate that mature T cells are required for cyclical idiotypic and anti-idiotypic responses to immunization with a T-independent antigen and suggest that the cyclical immune response may result from an interaction between idiotypic and anti-idiotypic cell clones.