35 research outputs found
Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class IIârich compartments lacking HLAâDO
To generate memory B cells bearing highâaffinity antibodies, naive B cells first encounter antigen in the T cellârich areas of secondary lymphoid organs. There, they are activated by antigenâspecific T cells and become germinal center (GC) founder B cells. GC founders enter the GC to become centroblasts that proliferate and mutate their BCR. Centroblasts differentiate into centrocytes that undergo selection, which requires both the recognition/capture of antigen on follicular dendritic cells and the presentation of processed antigen to GC T cells. Because at each stage of differentiation B cells act as antigenâpresenting cells, we analyzed their content of HLAâDR+ârich compartments (MIIC), as well as their expression of HLAâDM, which catalyzes peptide loading of class II molecules, and HLAâDO, which interacts with HLAâDM and focuses MHC class II peptide loading on antigens internalized by the BCR. Naive and memory B cells concentrate HLAâDR, âDM and âDO into compartments dispersed under the cell surface, which are identified by their expression of lysosomeâassociated membrane protein (Lamp)â1 as late endosomes/lysosomes. GC founders and GC B cells express larger Lampâ1+DR+ compartments that are concentrated in the juxtaânuclear region. These compartments express lower levels of HLAâDM and virtually no HLAâDO. Upon induction of a GC founder phenotype through the prolonged (days) coâligation of BCR and CD40, the naive B cell's peripheral DR+DM+Lampâ1+ compartments aggregate in a polar fashion close to the nucleus. Furthermore, HLAâDO expression virtually disappears, whereas low levels of HLAâDM remain coâlocalized with HLAâDR. AntiâÎș/λ antibodies, used as surrogate antigens, are promptly (minutes) endocytosed in naive, memory and GC B cells. Then, naive and memory B cells target the surrogate antigen to their peripheral HLAâDO+ MIIC, while GC B cells target it to their HLAâDO- MIIC aggregates. Taken together, our results show that human GC B cells differ from naive and memory B cells by their aggregated MIIC that lack HLAâD
PLoS One
Compared to the general population, HIV-infected patients are at higher risk of developing non-AIDS-defining cancers. Chronic HCV infection has also been associated with a higher risk than that of the general population of developing cancers other than hepatocarcinoma. Evaluation of the impact of HCV-related factors on non-AIDS-defining and non HCV-liver (NANL) related cancers among HIV/HCV co-infected patients are scarce. The aim of this study was to identify the impact of HIV/HCV clinical characteristics on NANL related cancers in a large cohort of HIV/HCV-coinfected patients followed from 2005 to 2017. Cox proportional hazards models with delayed entry were used to estimate factors associated with NANL related cancer. Among 1391 patients followed for a median of 5 years, 60 patients developed NANL related cancers, yielding an incidence rate of 8.9 per 1000 person-years (95% CI, [6.6-11.1]). By final multivariable analysis, after adjustment for sex, tobacco or alcohol consumption, baseline CD4 cell count and HCV sustained viral response (SVR), age and a longer duration since HIV diagnosis were independently associated with a higher risk of NANL related cancer (aHR for each additional year 1.10, 95% CI 1.06-1.14, p<0.0001 and 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). Duration of HCV infection, cirrhosis, HCV viral load, genotype and SVR were not associated with the occurrence of NANL related cancer. Among HIV/HCV-coinfected patients, age and the duration of HIV infection were the only characteristics found to be associated with the occurrence of NANL related cancer. In contrast, no association was observed with any HCV-related variables
Influenza A Virus Infection of Human Primary Dendritic Cells Impairs Their Ability to Cross-Present Antigen to CD8 T Cells
Influenza A virus (IAV) infection is normally controlled by adaptive immune responses initiated by dendritic cells (DCs). We investigated the consequences of IAV infection of human primary DCs on their ability to function as antigen-presenting cells. IAV was internalized by both myeloid DCs (mDCs) and plasmacytoid DCs but only mDCs supported viral replication. Although infected mDCs efficiently presented endogenous IAV antigens on MHC class II, this was not the case for presentation on MHC class I. Indeed, cross-presentation by uninfected cells of minute amounts of endocytosed, exogenous IAV was âŒ300-fold more efficient than presentation of IAV antigens synthesized by infected cells and resulted in a statistically significant increase in expansion of IAV-specific CD8 T cells. Furthermore, IAV infection also impaired cross-presentation of other exogenous antigens, indicating that IAV infection broadly attenuates presentation on MHC class I molecules. Our results suggest that cross-presentation by uninfected mDCs is a preferred mechanism of antigen-presentation for the activation and expansion of CD8 T cells during IAV infection
Fate of Antibody-Drug Conjugates in Cancer Cells
Abstract Antibody-Drug Conjugates (ADCs) are a class of cancer therapeutics that combines antigen specificity and potent cytotoxicity in a single molecule as they are comprised of an engineered antibody linked chemically to a cytotoxic drug. Four ADCs have received approval by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and can be prescribed for metastatic conditions while around 60 ADCs are currently enrolled in clinical trials. The efficacy of an ADC greatly relies on its intracellular trafficking and processing of its components to trigger tumor cell death. A limited number of studies have addressed these critical processes that both challenge and help foster the design of ADCs. This review highlights those mechanisms and their relevance for future development of ADCs as cancer therapeutics
Présentation antigénique par les molécules du complexe majeur d'histocompatibilité de classe II dans les lymphocytes B Humains
PARIS-BIUSJ-ThĂšses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF
The intracellular domain of CD44 promotes the fusion of macrophages
Macrophages seed all tissues in which they have the ability, in specific and rare instances, to fuse with themselves and to differentiate into osteoclasts in bone or into giant cells in chronic inflammatory reactions. Although these cells play a central role in osteoporosis and in foreign body rejection, respectively, the molecular mechanism used by macrophages to fuse remains poorly understood. Macrophages might also fuse with somatic and tumor cells to promote tissue repair and metastasis, respectively. We reported that CD44 expression is highly induced in macrophages at the onset of fusion in which it plays a role. We report now that the intracellular domain of CD44 (CD44ICD) is cleaved in macrophages undergoing fusion and that presenilin inhibitors prevent the release of CD44ICD and fusion. We also show that CD44ICD promotes the fusion of tissue macrophages and bone marrow-derived macrophages. Finally, we report that CD44ICD is localized in the nucleus of macrophages in which it promotes the activation of NF-ÎșB. These observations open avenues to study the role of CD44ICD in blood cells and tumors. (Blood. 2006;107: 796-805
Visualization of early influenza A virus trafficking in human dendritic cells using STED microscopy
<div><p>Influenza A viruses (IAV) primarily target respiratory epithelial cells, but can also replicate in immune cells, including human dendritic cells (DCs). Super-resolution microscopy provides a novel method of visualizing viral trafficking by overcoming the resolution limit imposed by conventional light microscopy, without the laborious sample preparation of electron microscopy. Using three-color Stimulated Emission Depletion (STED) microscopy, we visualized input IAV nucleoprotein (NP), early and late endosomal compartments (EEA1 and LAMP1 respectively), and HLA-DR (DC membrane/cytosol) by immunofluorescence in human DCs. Surface bound IAV were internalized within 5 min of infection. The association of virus particles with early endosomes peaked at 5 min when 50% of NP<sup>+</sup> signals were also EEA1<sup>+</sup>. Peak association with late endosomes occurred at 15 min when 60% of NP<sup>+</sup> signals were LAMP1<sup>+</sup>. At 30 min of infection, the majority of NP signals were in the nucleus. Our findings illustrate that early IAV trafficking in human DCs proceeds via the classical endocytic pathway.</p></div
Early trafficking events of IAV upon entry in human DCs.
<p>The schematic summarizes the endosomal trafficking pathway of IAV upon entry in human DCs, beginning with binding of IAV to receptors on the cell surface. Endocytosed IAV were targeted to EEA1<sup>+</sup> early endosomes within 5 min, followed by LAMP1<sup>+</sup> late endosomes where membrane fusion could take place. Release of viral ribonucleoproteins (vRNPs) led to nuclear translocation where viral replication could proceed.</p
Early trafficking events of IAV upon entry in human DCs.
<p>The schematic summarizes the endosomal trafficking pathway of IAV upon entry in human DCs, beginning with binding of IAV to receptors on the cell surface. Endocytosed IAV were targeted to EEA1<sup>+</sup> early endosomes within 5 min, followed by LAMP1<sup>+</sup> late endosomes where membrane fusion could take place. Release of viral ribonucleoproteins (vRNPs) led to nuclear translocation where viral replication could proceed.</p