Electron microscopy analysis of FcRγ localization after its capture by T cells by trogocytosis

T cells acquire various proteins from their cellular partners by the process of trogocytosis. We recently demonstrated that the FcγRIIIA receptor and its associated FcRγ are captured by T cells during their co-culture with FcγR-expressing target cells upon both antigen- or antibody-mediated stimulation. Interestingly, we found that FcR captured by T cells could bind ligands but did not transmit detectable intracellular signals or signaling-depending functions upon ligand binding suggesting their improper integration in the recipient T cell membrane. In this study, we provide morphological data in support of this hypothesis. Indeed, we show that the FcRγ-subunit, which we used as a fusion to GFP, was clearly present at the plasma membrane of donor cells, but was detected within structures that were in close contact of, but apparently not integrated in, the plasma membrane of recipient T cells

Innate immune basis for rift valley fever susceptibility in mouse models

Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies

Centre de recherches historiques – CRH

Hinnerk Bruhns, directeur de recherche au CNRSJean-Pierre Grossein, maître de conférences à l’Université Paris-VIII/Vincennes-Saint-Denis Max Weber : histoire, sociologie et économie Le séminaire a poursuivi les recherches entamées les années précédentes autour de trois axes : l’interprétation intrinsèque de l’œuvre wébérienne sur la base d’une étude des textes, l’investigation du champ intellectuel et du contexte plus largement dans lequel cette œuvre s’est construite, enfin les problèmes re..

Centre de recherches historiques – CRH

Hinnerk Bruhns, directeur de recherche au CNRSJean-Pierre Grossein, maître de conférences à l’Université Paris-VIII Max Weber : histoire, sociologie et économie Au cours de l’année, le séminaire a poursuivi les recherches entamées les années précédentes. Les problèmes d’interprétation et de réception de l’œuvre, ainsi que l’utilisation de concepts wébériens dans différents domaines des sciences sociales aujourd’hui ont constitué l’axe principal des différentes séances. Des problèmes de sociol..

Centre de recherches historiques – CRH

Jean Chapelot, directeur de recherche au CNRS Archéologie médiévale en France Cette année, l’objectif du séminaire était double : présenter des recherches récentes ; préparer le congrès de bilan de trente ans d’archéologie médiévale de la Société d’archéologie médiévale qui a eu lieu à Vincennes (Val-de-Marne) les 16-18 juin 2006. Dans la mesure du possible et grâce à la participation des intervenants, une documentation a été distribuée lors des séances. Comme les années précédentes, elle a é..

Centre de recherches historiques – CRH

Jean Chapelot, directeur de recherche au CNRS Archéologie médiévale en France Cette année, l’objectif du séminaire était double : présenter des recherches récentes ; préparer le congrès de bilan de trente ans d’archéologie médiévale de la Société d’archéologie médiévale qui a eu lieu à Vincennes (Val-de-Marne) les 16-18 juin 2006. Dans la mesure du possible et grâce à la participation des intervenants, une documentation a été distribuée lors des séances. Comme les années précédentes, elle a é..

Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells

Microbiota drive tertiary lymphoid tissue formation in mice lacking the nuclear hormone receptor Rorγt, leading to intestinal inflammation and wasting disease

Innate immune basis for rift valley fever susceptibility in mouse models

Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies

Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

An Engineered Human Fc variant With Exquisite Selectivity for FcγRIIIaV158 Reveals That Ligation of FcγRIIIa Mediates Potent Antibody Dependent Cellular Phagocytosis With GM-CSF-Differentiated Macrophages

IgG antibodies mediate the clearance of target cells via the engagement of Fc gamma receptors (FcγRs) on effector cells by eliciting antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP, respectively). Because (i) the IgG Fc domain binds to multiple FcγRs with varying affinities; (ii) even low Fc:FcγRs affinity interactions can play a significant role when antibodies are engaged in high avidity immune complexes and (iii) most effector cells express multiple FcγRs, the clearance mechanisms that can be mediated by individual FcγR are not well-understood. Human FcγRIIIa (hFcγRIIIa; CD16a), which exists as two polymorphic variants at position 158, hFcγRIIIaV158 and hFcγRIIIaF158, is widely considered to only trigger ADCC, especially with natural killer (NK) cells as effectors. To evaluate the role of hFcγRIIIa ligation in myeloid-derived effector cells, and in particular on macrophages and monocytes which express multiple FcγRs, we engineered an aglycosylated engineered human Fc (hFc) variant, Fc3aV, which binds exclusively to hFcγRIIIaV158. Antibodies formatted with the Fc3aV variant bind to the hFcγRIIIaV158 allotype with a somewhat lower KD than their wild type IgG1 counterparts, but not to any other hFcγR. The exceptional selectivity for hFcγRIIIaV158 was demonstrated by SPR using increased avidity, dimerized GST-fused versions of the ectodomains of hFcγRs and from the absence of binding of large immune complex (IC) to CHO cells expressing each of the hFcγRs, including notably, the FcγRIIIaF158 variant or the highly homologous FcγRIIIb. We show that even though monocyte-derived GM-CSF differentiated macrophages express hFcγRIIIa at substantially lower levels than the other two major activating receptors, namely hFcγRI or hFcγRIIa, Fc3aV-formatted Rituximab and Herceptin perform ADCP toward CD20- and Her2-expressing cancer cells, respectively, at a level comparable to that of the respective wild-type antibodies. We further show that hFcγRIIIa activation plays a significant role on ADCC by human peripheral monocytes. Our data highlight the utility of Fc3aV and other similarly engineered exquisitely selective, aglycosylated Fc variants toward other hFcγRs as tools for the detailed molecular understanding of hFcγR biology