H the development of CMBrain Endothelium and T Cell Proliferationin humans

H the development of CMBrain Endothelium and T Cell Proliferationin humans [36]. EC, at least from lymph nodes, can be modulators of immune responses as they express multiple peripheral tissue antigens, independent of the autoimmune regulator, AIRE [37], and can even induce anergy [38]. This, together with our observation of malarial 3PO antigen transfer to brain EC surfaces [3], opens more possibilities for endothelial-mediated immunopathological mechanisms in CM. The findings described here are not only a major interest for understanding CM pathogenesis but also other neuroinfections involving disruption of endothelial cell barriers such as neurocysticercosis and toxoplasmosis [39,40]. In summary, we have shown that human brain endothelium cells express molecules important for T cell stimulation and activation including CD40, MHC II and ICOSL. They readily can take up fluorescently labeled antigens via clathrin-coated pits and macropinocytosis. Moreover, these cells are able to bind to and promote the proliferation of allogeneic T cells in vitro. Data presented here supports the hypothesis that HBEC are able to act as APC. This is particularly pertinent in neuroinfections such as CM where the diameter of microvessels is smaller than the size of lymphocytes; the lymphocytes are in constant physical contact with the EC surface. Additionally, in the brains of both mice and human with CM, leukocytes (monocytes and T cells) become arrested in brain microvessels [2] providing further means for intimate EC/T cell interactions. It has long been established that CM is a T cell-dependent disease [41,42], with both CD4+ and CD8+ T cells playing key roles in CM pathogenesis [43,44]. Moreover, this cell-cell contact plays an important role in brain endothelial activation [45], as assessed notably by a dramatic increase in plasma levels endothelial microparticles at the time ofCM [46]. The data presented here, in combination with our recent demonstration that HBEC can transfer antigens from malarial-infected red blood cells onto their surface, thereby becoming a target for the immune response, provide key evidence for HBEC to act as antigen presenting cells with the presentation of malaria antigens by brain EC to T cells and the potential activation of cytotoxic mechanisms providing a new explanation for CM pathogenesis.Supporting Informationreduction in both CD4+ and CD8+ T cell proliferation. Graphical representation of fold increase in proliferation of aCD3/CD28 stimulated CD4+ and CD8+ T cells co-cultured with TNF/IFNc stimulated HBEC over unstimulated (control) CD4+ and CD8+ T cell proliferation. Proliferation assessed by CFSE following 6 days of co-culture either in 24 well plates (black bars) or in 0.4 mm transwells (white bars). (TIF)Figure S1 Separation of HBEC and PBMC results 1527786 in aAcknowledgmentsWe thank Gerard Chan for his technical assistance.Author ContributionsConceived and 68181-17-9 web designed the experiments: JW VC GG. Performed the 11967625 experiments: JW SO. Analyzed the data: JW SO. Contributed reagents/ materials/analysis tools: PC. Wrote the paper: JW VC GG.
The transcription factor Signal Transducer and Activator of Transcription (Stat) 3 is constitutively expressed in a wide variety of tissues. Stat3 is activated by various cytokines and growth factors such as OSM, LIF, IL-6, IL-10, IL-17, IL-23, leptin, EGF, and interferons, as well as the proto-oncogenes and oncogenes cSrc, c-Abl, Met, and ErbB2 [1]. Leukaemia inhibitory factor (LIF), which belongs.H the development of CMBrain Endothelium and T Cell Proliferationin humans [36]. EC, at least from lymph nodes, can be modulators of immune responses as they express multiple peripheral tissue antigens, independent of the autoimmune regulator, AIRE [37], and can even induce anergy [38]. This, together with our observation of malarial antigen transfer to brain EC surfaces [3], opens more possibilities for endothelial-mediated immunopathological mechanisms in CM. The findings described here are not only a major interest for understanding CM pathogenesis but also other neuroinfections involving disruption of endothelial cell barriers such as neurocysticercosis and toxoplasmosis [39,40]. In summary, we have shown that human brain endothelium cells express molecules important for T cell stimulation and activation including CD40, MHC II and ICOSL. They readily can take up fluorescently labeled antigens via clathrin-coated pits and macropinocytosis. Moreover, these cells are able to bind to and promote the proliferation of allogeneic T cells in vitro. Data presented here supports the hypothesis that HBEC are able to act as APC. This is particularly pertinent in neuroinfections such as CM where the diameter of microvessels is smaller than the size of lymphocytes; the lymphocytes are in constant physical contact with the EC surface. Additionally, in the brains of both mice and human with CM, leukocytes (monocytes and T cells) become arrested in brain microvessels [2] providing further means for intimate EC/T cell interactions. It has long been established that CM is a T cell-dependent disease [41,42], with both CD4+ and CD8+ T cells playing key roles in CM pathogenesis [43,44]. Moreover, this cell-cell contact plays an important role in brain endothelial activation [45], as assessed notably by a dramatic increase in plasma levels endothelial microparticles at the time ofCM [46]. The data presented here, in combination with our recent demonstration that HBEC can transfer antigens from malarial-infected red blood cells onto their surface, thereby becoming a target for the immune response, provide key evidence for HBEC to act as antigen presenting cells with the presentation of malaria antigens by brain EC to T cells and the potential activation of cytotoxic mechanisms providing a new explanation for CM pathogenesis.Supporting Informationreduction in both CD4+ and CD8+ T cell proliferation. Graphical representation of fold increase in proliferation of aCD3/CD28 stimulated CD4+ and CD8+ T cells co-cultured with TNF/IFNc stimulated HBEC over unstimulated (control) CD4+ and CD8+ T cell proliferation. Proliferation assessed by CFSE following 6 days of co-culture either in 24 well plates (black bars) or in 0.4 mm transwells (white bars). (TIF)Figure S1 Separation of HBEC and PBMC results 1527786 in aAcknowledgmentsWe thank Gerard Chan for his technical assistance.Author ContributionsConceived and designed the experiments: JW VC GG. Performed the 11967625 experiments: JW SO. Analyzed the data: JW SO. Contributed reagents/ materials/analysis tools: PC. Wrote the paper: JW VC GG.
The transcription factor Signal Transducer and Activator of Transcription (Stat) 3 is constitutively expressed in a wide variety of tissues. Stat3 is activated by various cytokines and growth factors such as OSM, LIF, IL-6, IL-10, IL-17, IL-23, leptin, EGF, and interferons, as well as the proto-oncogenes and oncogenes cSrc, c-Abl, Met, and ErbB2 [1]. Leukaemia inhibitory factor (LIF), which belongs.

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