| 1. |
- Avila-Carino, Javier Federico
(författare)
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Characteristics of EBV-infected B cell lines and B-CLL clones which determine their interaction with lymphocytes
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The results concerning T Iymphocyte mediated recognition of Epstein-Barr virus (EBV) carrying Burkitt Iymphoma (BL) cell lines and EBV-infected chronic Iymphocytic leukemia (CLL) B cells contribute to the understanding of the generally harmless host-EBV interaction and may be extrapolated to the fate of normal B cells after EBV infection. The phenotype of EBV negative BL lines resembles resting B cells. We have observed that the virus-positive sublines stimulated allogeneic T cells more efficiently compared to the original virus-negative BL cells. We compared also the allostimulatory capacity of sublines developed from one EBV carrying BL, which were selected for differences in phenotype and expression of EBV encoded proteins. The sublines that have the latency I program express only EBNA-I, are similar to resting B cells and do not stimulate allogeneic T Iymphocytes, whilst the sublines that exhibit the latency Ill program express the viral proteins EBNA-2 to -6 and LMP-1, have the phenotype of activated B cells and stimulate the allogeneic T Iymphocytes. Surface marker analysis of the populations suggested that the T cell stimulatory capacity correlated with the expression of the integrins LFA-I and LFA-3. The T cell response to the EBV-carrying BL lines and to the LCLs was not EBV specific since EBV-seronegative donors responded as strongly as the EBV-seropositive ones. The significance of this results is the demonstration that the EBV genome in the BL cells does not influence their interaction with allogeneic T Iymphocytes as long as they keep the latency I program (resting B cell phenotype). B-CLL is clonal and each patient represents thus a different B-cell clone. Clones differ in their sensitivity to experimental EBV infection but even if they are infected they yield rarely immortalized lines. Their degree of sensitivity to EBV infection suggests differences in the maturation state of the CLL cells. It may therefore reflect the variation in the response to EBV infection within a normal B cell population. The majority of the CLL clones has low susceptibility to EBV infection and do not stimulate proliferation of T Iymphocytes. Exposure of the EBV-infected CLL cells to a mixture of B cell mitogens (SAC-lL2-tioredoxin) stimulated T Iymphocytes. Usually EBV-infected CLL cells express EBNA-1 to -6 but not LMP-l, suggesting a new pattern of viral latency. Analysis of surface markers, adhesion and costimulatory molecules on the cells of the clones did not correlate with their T cell stimulatory capacity. Comparison of cytokine production by the differently activated CLL cells showed that the EBV-infected CLL clones with high susceptibility to be infected have high frequency of cells producing all the searched cytokines (IL-1a, IL-1,b, IL-2, IL-4, IL-6, IL-10, IL-13, IFN-y, TNF-a, TNF-b and GM-CSF), whilst the clones with low susceptibility to EBV, the diversity and frequency of the cytokines was lower. In general, the frequency of cytokine-expressing B- CLL cells correlated with their capacity to stimulate T cells. The in vitro EBV-infected CLL clones were Iysed with the same efficiency as the established LCLs by the autologous EBV specific T Iymphocytes. It can be assumed therefore that if such cells are infected in vivo, they eventually become activated, express viral encoded proteins and are eliminated by the T cell response.
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| 2. |
- Bergonzini, Anna, 1990-, et al.
(författare)
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The challenge of establishing immunocompetent human intestinal 3D models
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Expression of typhoid toxin in Salmonella Typhimurium causes DNA damage, activating the DNA damage response (DDR), in absence of an inflammatory response in the colonic mucosa of infected mice. The anti-inflammatory effect is tissue specific and is not observed in the liver, suggesting that the local immune microenvironment modulates the DDR outcome.To assess the role of the immune cells in the DDR outcome induced by the genotoxigenic Salmonella, we have initiated the development of an immunocompetent 3D colonic mucosal model based on a collagen matrix containing colonic fibroblasts and different subtypes of immune cells, overlayed with colonic epithelial cells.Embedding of peripheral blood mononuclear cells in the collagen matrix did not influenced either the tissue integrity or the activation of the DDR, observed exclusively upon infection with the genotoxigenic strain. However, embedding of T cells, monocytes, or non-polarized macrophages altered the pattern of the DDR and the toxin specific effect was lost. Presence of macrophages was further associated with alteration of the epithelial layer integrity. This effect was infection-dependent, but not toxin specific.Our data demonstrated that addition of immune cells to a 3D mucosal model altered the DDR induced by a genotoxigenic bacterium, highlighting the need to develop and optimize immunocompetent in vitro models.
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| 3. |
- Cortes-Bratti, Ximena, et al.
(författare)
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Thioredoxin 80-activated-monocytes (TAMs) inhibit the replication of intracellular pathogens
- 2011
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Thioredoxin 80 (Trx80) is an 80 amino acid natural cleavage product of Trx, produced primarily by monocytes. Trx80 induces differentiation of human monocytes into a novel cell type, named Trx80-activated-monocytes (TAMs).PRINCIPAL FINDINGS: In this investigation we present evidence for a role of TAMs in the control of intracellular bacterial infections. As model pathogens we have chosen Listeria monocytogenes and Brucella abortus which replicate in the cytosol and the endoplasmic reticulum respectively. Our data indicate that TAMs efficiently inhibit intracellular growth of both L. monocytogenes and B. abortus. Further analysis shows that Trx80 activation prevents the escape of GFP-tagged L. monocytogenes into the cytosol, and induces accumulation of the bacteria within the lysosomes. Inhibition of the lysosomal activity by chloroquine treatment resulted in higher replication of bacteria in TAMs compared to that observed in control cells 24 h post-infection, indicating that TAMs kill bacteria by preventing their escape from the endosomal compartments, which progress into a highly degradative phagolysosome.SIGNIFICANCE: Our results show that Trx80 potentiates the bactericidal activities of professional phagocytes, and contributes to the first line of defense against intracellular bacteria.
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| 4. |
- Lopez Chiloeches, Maria, et al.
(författare)
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Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.
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| 5. |
- Stratoulias, Vassilis, et al.
(författare)
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ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- 2023
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 26:6, s. 1008-1020
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Tidskriftsartikel (refereegranskat)abstract
- Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1- microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
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