Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma

Heterogeneite fonctionnelle des lymphocytes B de leucemie lymphoiede chronique de type B : interactions entre signaux non specifiques

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

CpG-Activated Regulatory B-Cell Progenitors Alleviate Murine Graft-Versus-Host-Disease

International audienceDevelopment of Graft Versus Host Disease (GVHD) represents a major impediment in allogeneic hematopoietic stem cell transplantation (HSCT). The observation that the presence of bone marrow and circulating hematogones correlated with reduced GVHD risks prompted us to evaluate whether B-cell progenitors, which provide protection in various autoimmune disease models following activation with the TLR-9 agonist CpG (CpG-proBs), could likewise reduce this allogeneic disorder. In a murine model of GVHD that recapitulates an initial phase of acute GVHD followed by a phase of chronic sclerodermatous GVHD, we found that CpG-proBs, adoptively transferred during the initial phase of disease, reduced the diarrhea score and mostly prevented cutaneous fibrosis. Progenitors migrated to the draining lymph nodes and to the skin where they mainly differentiated into follicular B cells. CpG activation and IFN-γ expression were required for the protective effect, which resulted in reduced CD4 + T-cell-derived production of critical cytokines such as TGF-β, IL-13 and IL-21. Adoptive transfer of CpG-proBs increased the T follicular regulatory to T follicular helper (Tfr/Tfh) ratio. Moreover, CpG-proBs privileged the accumulation of IL-10-positive CD8 + T cells, B cells and dendritic cells in the skin. However, CpG-proBs did not improve survival. Altogether, our findings support the notion that adoptively transferred CpG-proBs exert immunomodulating effect that alleviates symptoms of GVHD but require additional anti-inflammatory strategy to improve survival

Differential effect of FasL on GvHD disease according to its source

International audienceObjective: Hematopoietic stem cell transplantation is a potentially curative treatment for hematologic malignancies. An important limitation of its use is the frequent occurrence of graft versus host disease (GvHD). GvHD is associated with complex interactions between innate and adaptive immunity. The incidence of GvHD is 40 to 80% depending on donor-and transplant-characteristics. A number of pathways have been described on allogeneic T cell-mediated cytotoxicity, including the Fas/Fas ligand (FasL) pathway. However, the overall mechanistic findings on how FasL expression in donor cells affects target tissues remains poorly characterized. Methods: We used a well-defined CD4 and CD8-dependent sclerodermatous GvHD model. GvHD is induced by transplantation of low doses of T-and B-cell depleted BM cells and splenocytes from C57BL/6 mice into lethally irradiated BALB/c mice. Colon and skin samples were analyzed by flux cytometry and H&ES staining of fixed sections. Serum cytokines were measured by Multiplex ELISA. Results: Recipient from Fasl-KO BM mice exhibited exacerbate gut acute GvHD (diarrhea significantly higher compared to WT-BM recipient mice). Serum analysis at Day 10 post transplantation (PT) revealed a drastically reduced IL-18 level in these mice compared to WT-BM recipient mice. Cellular and histological analysis of colon biopsies showed significantly higher frequency of CD8 T cells and lymphocytic infiltrates in Fasl KO-BM recipient mice as compared to WT-BM. Recipients of FasL deficient T cells (transplanted with WT BM) displayed significantly reduced symptoms of acute (diarrhea) and chronic GvHD (skin lesion). Pathological skin analysis at Day 34 PT revealed that, unlike syngeneic control mice where cellular infiltrate was mostly of myeloid origin, the infiltrate in mice with GVHD included myeloid-cells and T-cells in similar proportion. In recipients of Fasl KO-splenocytes, proportions of Treg (FoxP3+CD25+) were significantly increased while those of IFN-γ + CD4 T-cells were significantly decreased as compared to WT-splenocytes recipients; suggesting a regulatory environment. Conclusion: These results indicate that FasL expression, either in BM or in in splenocytes, acts differentially in GvHD. FasL expression by donor myeloid cells confers protection from aGvHD via the production of IL-18. In contrast, FasL expression by donor T cells mediates cytotoxicity

Differential effect of FasL on GvHD disease according to its source

International audienceObjective: Hematopoietic stem cell transplantation is a potentially curative treatment for hematologic malignancies. An important limitation of its use is the frequent occurrence of graft versus host disease (GvHD). GvHD is associated with complex interactions between innate and adaptive immunity. The incidence of GvHD is 40 to 80% depending on donor-and transplant-characteristics. A number of pathways have been described on allogeneic T cell-mediated cytotoxicity, including the Fas/Fas ligand (FasL) pathway. However, the overall mechanistic findings on how FasL expression in donor cells affects target tissues remains poorly characterized. Methods: We used a well-defined CD4 and CD8-dependent sclerodermatous GvHD model. GvHD is induced by transplantation of low doses of T-and B-cell depleted BM cells and splenocytes from C57BL/6 mice into lethally irradiated BALB/c mice. Colon and skin samples were analyzed by flux cytometry and H&ES staining of fixed sections. Serum cytokines were measured by Multiplex ELISA. Results: Recipient from Fasl-KO BM mice exhibited exacerbate gut acute GvHD (diarrhea significantly higher compared to WT-BM recipient mice). Serum analysis at Day 10 post transplantation (PT) revealed a drastically reduced IL-18 level in these mice compared to WT-BM recipient mice. Cellular and histological analysis of colon biopsies showed significantly higher frequency of CD8 T cells and lymphocytic infiltrates in Fasl KO-BM recipient mice as compared to WT-BM. Recipients of FasL deficient T cells (transplanted with WT BM) displayed significantly reduced symptoms of acute (diarrhea) and chronic GvHD (skin lesion). Pathological skin analysis at Day 34 PT revealed that, unlike syngeneic control mice where cellular infiltrate was mostly of myeloid origin, the infiltrate in mice with GVHD included myeloid-cells and T-cells in similar proportion. In recipients of Fasl KO-splenocytes, proportions of Treg (FoxP3+CD25+) were significantly increased while those of IFN-γ + CD4 T-cells were significantly decreased as compared to WT-splenocytes recipients; suggesting a regulatory environment. Conclusion: These results indicate that FasL expression, either in BM or in in splenocytes, acts differentially in GvHD. FasL expression by donor myeloid cells confers protection from aGvHD via the production of IL-18. In contrast, FasL expression by donor T cells mediates cytotoxicity

PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation

International audienc