Renal CD169++ resident macrophages are crucial for protection against acute systemic candidiasis.

Disseminated candidiasis remains as the most common hospital-acquired bloodstream fungal infection with up to 40% mortality rate despite the advancement of medical and hygienic practices. While it is well established that this infection heavily relies on the innate immune response for host survival, much less is known for the protective role elicited by the tissue-resident macrophage (TRM) subsets in the kidney, the prime organ for Candida persistence. Here, we describe a unique CD169++ TRM subset that controls Candida growth and inflammation during acute systemic candidiasis. Their absence causes severe fungal-mediated renal pathology. CD169++ TRMs, without being actively involved in direct fungal clearance, increase host resistance by promoting IFN-γ release and neutrophil ROS activity.

Type 1 Conventional CD103+ Dendritic Cells Control Effector CD8+ T Cell Migration, Survival, and Memory Responses During Influenza Infection.

Type 1 conventional CD103+ dendritic cells (cDC1) contribute significantly to the cytotoxic T lymphocyte (CTL) response during influenza virus infection; however, the mechanisms by which cDC1s promote CTL recruitment and viral clearance are unclear. We demonstrate that cDC1 ablation leads to a deficient influenza-specific primary CD8+ T cell response alongside severe pulmonary inflammation, intensifying susceptibility to infection. The diminished pulmonary CTL population is not only a consequence of reduced priming in the lymph node (LN), but also of dysregulated CD8+ T cell egression from the LN and reduced CD8+ T cell viability in the lungs. cDC1s promote S1PR expression on CTLs, a key chemokine receptor facilitating CTL LN egress, and express high levels of the T cell survival cytokine, IL-15, to support CTL viability at the site of infection. Moreover, cDC1 ablation leads to severe impairment of CD8+ T cell memory recall and cross-reactive protection, suggesting that cDC1 are not only involved in primary T cell activation, but also in supporting the development of effective memory CD8+ T cell precursors. Our findings demonstrate a previously unappreciated and multifaceted role of CD103+ DCs in controlling pulmonary T cell-mediated immune responses.

A Discrete Subset of Monocyte-Derived Cells among Typical Conventional Type 2 Dendritic Cells Can Efficiently Cross-Present.

Dendritic cells (DCs) and macrophages (Mϕs) share close developmental pathways and functional features, leading to blurring of the boundaries between these two cell lineages. However, a deeper understanding of DC and Mϕ ontogeny and more refined phenotypic and functional characterizations have helped to delineate pre-DC-derived conventional DCs (cDCs), including cDC1s and cDC2s, from monocyte-derived Mϕs. Here, we further refine DC/Mϕ cell classification and report that classically defined cDC2s contain a discrete population of monocyte-derived migratory antigen-presenting cells with Mϕ phenotype but functional DC features, including cross-presentation.

Role and contribution of pulmonary CD103+ dendritic cells in the adaptive immune response to Mycobacterium tuberculosis.

Despite international control programmes, the global burden of tuberculosis remains enormous. Efforts to discover novel drugs have largely focused on targeting the bacterium directly. Alternatively, manipulating the host immune response may represent a valuable approach to enhance immunological clearance of the bacilli, but necessitates a deeper understanding of the immune mechanisms associated with protection against Mycobacterium tuberculosis infection. Here, we examined the various dendritic cells (DC) subsets present in the lung and draining lymph nodes (LN) from mice intra-tracheally infected with M. tuberculosis. We showed that although limited in number, pulmonary CD103+ DCs appeared to be involved in the initial transport of mycobacteria to the draining mediastinal LN and subsequent activation of T cells. Using CLEC9A-DTR transgenic mice enabling the inducible depletion of CD103+ DCs, we established that this DC subset contributes to the control of mycobacterial burden and plays a role in the early activation of T cells, in particular CD8+ T cells. Our findings thus support a previously unidentified role for pulmonary CD103+ DCs in the rapid mobilization of mycobacteria from the lungs to the draining LN soon after exposure to M. tuberculosis, which is a critical step for the development of the host adaptive immune response.

Transient ablation of alveolar macrophages leads to massive pathology of influenza infection without affecting cellular adaptive immunity.

Alveolar macrophages (AMs), localized at the pulmonary air-tissue interface, are one of the first lines of defense that interact with inhaled airborne pathogens such as influenza viruses. By using a new CD169-DTR transgenic mouse strain we demonstrate that specific and highly controlled in vivo ablation of this myeloid cell subset leads to severe impairment of the innate, but not adaptive, immune responses and critically affects the progression of the disease. In fact, AM-ablated mice, infected with a normally sublethal dose of PR8 influenza virus, showed dramatically increased virus load in the lungs, severe airway inflammation, pulmonary edema and vascular leakage, which caused the death of the infected animals. Our data highlight the possibilities for new therapeutic strategies focusing on modulation of AMs, which may efficiently boost innate responses to influenza infections.

The nuclear-factor kappaB pathway is activated in pterygium.

PURPOSE: Pterygium is a prevalent ocular surface disease with unknown pathogenesis. The authors investigated the role of nuclear factor kappa B (NF-κB) transcription factors in pterygium. METHODS: Surgically excised primary pterygia were studied compared with uninvolved conjunctiva tissues. NF-κB activation was evaluated using Western blot analysis, ELISA, and DNA-binding assays. Primary pterygium fibroblasts were treated with TNF-α (20 ng/mL), and NF-κB activation was evaluated using immunocytochemistry, Western blot analysis, phospho-IκBα ELISA, and DNA-binding assays. TNF-α stimulation of NF-κB target genes RelB, NFKB2, RANTES, MCP-1, ENA-78, MMP-1, MMP-2, and MMP-3 in pterygium fibroblasts was compared with that in primary tenon fibroblasts by real-time PCR. RESULTS: Phosphorylation of IκBα (Ser32) was increased in pterygia tissues compared with uninvolved conjunctiva tissues, as determined by Western blot analysis and ELISA. IκBα expression was decreased, whereas nuclear RelA and p50 DNA-binding capacities were increased. Within 30 minutes of treatment with TNF-α, pterygium fibroblasts showed increased IκBα phosphorylation and nuclear translocation of RelA and p50. Treatment with TNF-α beyond 12 hours resulted in increased nuclear expression of RelB, p100, and p52. Furthermore, the upregulation of RANTES, MCP-1, ENA-78, MMP-1, MMP-2, and MMP-3 expression was more pronounced in TNF-α-treated pterygium fibroblasts than in tenon fibroblasts. CONCLUSIONS: The NF-κB pathway is shown for the first time to be activated in pterygia tissues compared with normal conjunctiva tissues. Stimulation by the inflammatory cytokine TNF-α can activate both canonical and noncanonical NF-κB pathways in pterygium fibroblasts with concomitant upregulation of NF-κB target genes.

A helix swapping study of two protein cages.

Protein cages have been the focus of studies across multiple scientific disciplines. They have been used to deliver drugs, as templates for nanostructured materials, as substrates in the development of bio-orthogonal chemistry, and to restrict diffusion to study spatially confined reactions. Although their monomers fold into four-helix bundle structures, two cage proteins, DPS and BFR, self-assemble to form a 12-mer with tetrahedral symmetry and an octahedrally symmetric 24-mer, respectively. These monomers share strong similarities of both sequence and tertiary structure. However, they differ in the presence of a short additional helix. In BFR, the fifth helix is at the C-terminus and is positioned along the 4-fold symmetry axis, whereas with DPS, an extra helix helps to define the 2-fold axis in the cage and is located between the second and third helices in the monomer bundle. In an attempt to investigate if these short helices govern protein assembly, mutants were designed and produced that delete and swap these minidomains. All mutants form highly helical structures that unfold cooperatively as evidenced by thermal melting followed by circular dichroism. Dynamic light scattering, size exclusion chromatography, and sedimentation equilibrium experiments demonstrated that although many of the BFR mutants do not self-assemble and form lower-order complexes, many DPS mutants could form cages despite their unnatural design. Taken together, our data indicate that the BC helix is less important than the E helix for overall cage self-assembly, suggesting that dimerization may not play a role in nanostructure formation that is as key as previously assumed. Additionally, we found that fusing the minidomain from BFR onto DPS results in a mutant that assembles into a homogeneous population of a novel protein oligomer. This assembled cage while still formed from 12 subunits is larger in overall shape than that of the native protein.