Thymic Overexpression of CD40 Ligand Disrupts Normal Thymic Epithelial Organization (original) (raw)
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Developmental Immunology, 2002
Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4+and CD8+thymocytes in adult mice (39±10×106in transgenic mice and 12±5×106in age-matched controls). Furthermore, thymocyte export was disturbed.
European Journal of Immunology, 2006
In this report, we show that the formation of germinal center (GC)-like structures to thymus-independent type 2 antigens in mice depends on intact signals through CD40, but does not depend on T cell-derived CD40-ligand (CD154). In addition, we show that follicular dendritic cells (FDC) are also critical to thymus-independent GC formation, as their depletion by blockade of lymphotoxin-b receptor signals abrogated GC development unless the responding B cells bound antigen with high affinity. Further evidence that immune complexes drove this CD40-dependent B cell proliferation was provided by the observation that an antibody that detects immune complexes containing complement component 4 on FDC also inhibited thymus-independent GC formation when injected in vivo at the time of immunization. Finally, we show that thymus-independent B cell proliferation was associated with class switching to IgG3, as IgG3 + antigen-specific switched B cells could be visualized directly in GC, suggesting that immune complexes can provide the signals for class switching within GC in the absence of CD154.
An Essential Role for gp39, the Ligand for CD40, in Thymic Selection
The Journal of Experimental Medicine, 1995
The interactions between CD40 on B cells and its ligand gp39 on activated T helper cells are known to be essential for the development of thymus-dependent humoral immunity. However, CD40 is also functionally expressed on thymic epithelial cells and dendritic cells, suggesting that gp39-CD40 interactions may also play a role in thymic education, the process by which self-reactive cells are deleted from the T cell repertoire. Six systems of negative selection were studied for their reliance on gp39-CD40 interactions to mediate negative selection. In all cases, when the antigen/superantigen was endogenously expressed (in contrast to exogenously administered), negative selection was blocked by loss of gp39 function. Specifically, blockade of gp39-CD40 interactions prevented the deletion of thymocytes expressing V[33, V[311, and V[312, specificities normally deleted in BALB/c mice because of the endogenous expression of minor lymphocyte-stimulating determinants. Independent verification of a role of gp39 in negative selection was provided by studies in gp39-deficient mice where alterations in T cell receptor (TCP,) V[3 expression were also observed. Studies were also performed in the AND TCR. transgenic (Tg) mice, which bear the Vti11,V[33 TCR. and recognize both pigeon cytochrome c (PCC)/IE k and H-2A s. Neonatal administration ofanti-gp39 to AND TCP, Tg mice that endogenously express H-2A s or endogenously produce PCC prevented the deletion of TCR Tg T cells. In contrast, deletion mediated by high-dose PCC peptide antigen (administered exogenously) in AND TCI< mice was unaltered by administration ofanti-gp39. In addition, deletion by Staphylococcus enterotoxin B in conventional mice was also unaffected by anti-gp39 administration, gp39 expression was induced on thymocytes by mitogens or by antigen on TCR Tg thymocytes. Immunohistochemical analysis of B7-2 expression in the thymus indicated that, in the absence of gp39, B7-2 expression was substantially reduced. Taken together, these data suggest that gp39 may influence negative selection through the regulation of costimulatory molecule expression. Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR. engagement and costimulation.
Acta Histochemica, 1996
Programmed cell death or apoptosis is a process in which a specific cell population is eliminated from the living organism in response to a variety of extracellular and intracellular stimuli. Altering the apoptotic threshold may have the potential to change the natural progression of some diseases, including cancer, viral infection, autoimmune and neurodegenerative disorders and AIDS. Biochemical and morphological events, such as blebbing of the cell membrane, activation of proteases in the cytoplasm and fragmentation of nuclear DNA are initiated in this process (1-4). However, it is not clear how the biochemical events taking place in different cell compartments, coordinate during programmed cell death. Using electron microscopy, fluorescent-laser confocal microscopy, and 3D reconstruction, we carried out a comprehensive analysis of intracellular organization of an apoptotic cell correlated with critical biochemical processes during apoptosis. Using immortalized ovarian follicular cells as a model system (1, 2), we found that unlike in normal growing cells, during apoptosis the most abundant proteases, the proteasomes, (5, 6) are excluded from the nucleus and accumulate in the cell periphery, within the apoptotic blebs (7). This process involves reorganization of the actin cytoskeleton, which forms a spherical network, separating the apoptotic blebs from the cytoplasmic organelles, such as mitochondria and lipid droplets, remaining in the perinuclear region. We suggest that formation of apoptotic blebs, redistribution of pro
Cytokine crosstalk for thymic medulla formation
Current Opinion in Immunology, 2011
The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. Recent studies have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance.
Leukemia Research, 1989
The thymus is populated by various Ia ÷ cell populations, including epithelial cells, macrophages and dendritic cells. Thymic cell suspensions were stained with an anti-Ia antibody and shown by cytofluorometry to contain a small number of strongly Ia + cells characterized by a large diameter. The cell population was separated with the aid of the fluorescence-activated cell sorter (FACS) and characterized. They were shown to express high levels of membranal Ia antigens; they demonstrated ATPase activity and displayed the ultrastructural features characteristic of the previously described thymic interdigitating cells. C57BL/6 mice were submitted to various regimens of X-irradiation. Whereas exposure to a single dose of X-irradiation was followed by an increase in the percentage of strongly Ia ÷ cells, exposure to a leukemogenic regimen offractionated X-irradiation led to a decrease in the percentage and absolute numbers of these cells in the thymus. Of the C57BL/6 mice that were irradiated with fractionated X-irradiation, 77% developed leukemia. Intravenous injection of syngeneic bone marrow one day following the last irradiation or protection of the femur during irradiation prevented both the appearance of leukemia and the disappearance of interdigitating cells. Therefore an inverse correlation between the presence of thymic dendritic cells and the incidence of leukemia in C57BL/6 mice could be demonstrated. These findings are discussed in relation to the putative role of dendritic cells in the thymus.