FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis.

FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluate cancer growth in mice with low, normal, or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma.

Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2.

Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing.

The role of the antigen processing machinery in the regulation and trafficking of intracellular -Toll-like receptor molecules.

Intracellular Toll-like receptors (TLRs) are key components of the innate immune system. Their expression in antigen-presenting cells (APCs), and in particular dendritic cells (DCs), makes them critical in the induction of the adaptive immune response. In DCs, they interact with the chaperone UNC93B1 that mediates their trafficking from the endoplasmic reticulum (ER) to endosomes where they are cleaved by proteases and activated.

Microglial P2X4 receptors promote ApoE degradation and contribute to memory deficits in Alzheimer's disease.

Numerous evidences support that microglia contributes to the progression of Alzheimer's disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated.

In Vitro and In Vivo Assays to Evaluate Dendritic Cell Phagocytic Capacity.

Phagocytosis is a process by which specific immune cells such as macrophages or dendritic cells engulf large particles. It is an important innate immune defense mechanism for removing a wide variety of pathogens and apoptotic cells. Following phagocytosis, nascent phagosomes are formed which, when fused to lysosome to become phagolysosome containing acidic proteases, will allow the degradation of ingested material.

Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance.

Antigenic peptides derived from introns are presented on major histocompatibility (MHC) class I molecules, but how these peptides are produced is poorly understood. Here, we show that an MHC class I epitope (SL8) sequence inserted in the second intron of the β-globin gene in a C57BL/6 mouse (HBB) generates immune tolerance. Introduction of SL8-specific CD8 T cells derived from OT-1 transgenic mice resulted in a threefold increase in OT-1 T cell proliferation in HBB animals, as compared to wild-type animals.

The Autophagy Receptor TAX1BP1 (T6BP) improves antigen presentation by MHC-II molecules.

CD4 T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized.

A tribute to Nilabh Shastri and a special issue on antigen processing and presentation in Paris (APP10, Paris 2019).

The Special Issue is dedicated to the 10th Antigen Processing and Presentation Workshop, which took place at Institut Cochin in Paris from May 28th to June 2nd, 2019. It contains several reviews or original articles from contributors to this workshop. It is also a vibrant Tribute to Nilabh Shastri, founder of the APP Workshops, who untimely passed away in 2021 and is deeply missed by his colleagues and friends.

Substrate-specific presentation of MHC class I-restricted antigens via autophagy pathway.

The accumulation of protein aggregates is toxic and linked to different diseases such as neurodegenerative disorders, but the role of the immune system to target and destroy aggregate-carrying cells is still relatively unknown. Here we show a substrate-specific presentation of antigenic peptides to the direct MHC class I pathway via autophagy. We observed no difference in presentation of peptides derived from the viral EBNA1 protein following suppression of autophagy by knocking down Atg5 and Atg12.

The role of endoplasmic reticulum stress in the MHC class I antigen presentation pathway of dendritic cells.

Dendritic cells (DCs) have the unique capacity to link innate to adaptive immunity. While most cells that express major histocompatibility (MHC) molecules are able to present antigens to activated T cells, DCs possess the means for presenting antigens to naïve T cells, and, as such, are able to instruct T cells to initiate immune response. There are two cascades of events necessary for DCs to start their instructive function.

Chloroquine inhibits pro-inflammatory effects of heme on macrophages and invivo.

Background: Chloroquine has been used successfully to treat Malaria, including by chloroquine-resistant Plasmodium sp., indicating that it has effects on disease itself. Since heme has inflammatory effects and contributes to the pathogenesis of hemolytic diseases, we hypothesize that the anti-inflammatory effect of chloroquine is partially due to its inhibitory effect on heme-induced macrophage activation and on inflammatory tissue damage.

B cell zone reticular cell microenvironments shape CXCL13 gradient formation.

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13 follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B cell trafficking.

Conditionally Controlling Human TLR2 Activity via Trans-Cyclooctene Caged Ligands.

Toll-like receptors (TLRs) are key pathogen sensors of the immune system. Their activation results in the production of cytokines, chemokines, and costimulatory molecules that are crucial for innate and adaptive immune responses. In recent years, specific (sub)-cellular location and timing of TLR activation have emerged as parameters for defining the signaling outcome and magnitude.

TLR7 trafficking and signaling in B cells is regulated by the MHCII-associated invariant chain.

Toll-like receptor 7 (TLR7) is an endosomal receptor that recognizes single-stranded RNA from viruses. Its trafficking and activation is regulated by the endoplasmic reticulum (ER) chaperone UNC93B1 and lysosomal proteases. UNC93B1 also modulates major histocompatibility complex class II (MHCII) antigen presentation, and deficiency in MHCII protein diminishes TLR9 signaling.

In Vitro Digestion with Proteases Producing MHC Class II Ligands.

Proteases generate peptides that bind to MHC class II molecules to interact with a wide diversity of CD4 T cells. They are expressed in dedicated organelles: endosomes and lysosomes of professional antigen-presenting cells (pAPCs) such as B cells, macrophages, and dendritic cells. The identification of endosomal proteases which produce antigenic peptides is important for example for better vaccination and to prevent autoimmune diseases.

The Isoform Selective Roles of PI3Ks in Dendritic Cell Biology and Function.

Phosphoinositide-3 kinases (PI3Ks) generate 3-phosphorylated phosphoinositide lipids that are implicated in many biological processes in homeostatic states and pathologies such as cancer, inflammation and autoimmunity. Eight isoforms of PI3K exist in mammals and among them the class I PI3K, p110γ, and PI3Kδ, and class III Vps34 being the most expressed and well characterized in immune cells. Following engagement of pathogen recognition receptors (PRRs), PI3Ks coordinate vital cellular processes of signaling and vesicular trafficking in innate phagocytes such as macrophages and professional antigen presenting dendritic cells (DCs).

Author Correction: TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

The originally published version of this Article contained an error in the subheading "Microglial GR does not affect DN loss triggered by TLR4 and TLR7," which was incorrectly given as "Microglial GR does affect DN loss triggered by TLR2 and TLR4". This has now been corrected in both the PDF and HTML versions of the Article.

TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

Inflammation is a characteristic feature of Parkinson's disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls.

STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells.

Antigen cross-presentation by dendritic cells (DC) stimulates cytotoxic T cell activation to promote immunity to intracellular pathogens, viruses and cancer. Phagocytosed antigens generate potent T cell responses, but the signalling and trafficking pathways regulating their cross-presentation are unclear. Here, we show that ablation of the store-operated-Ca-entry regulator STIM1 in mouse myeloid cells impairs cross-presentation and DC migration in vivo and in vitro.