ABSTRACT
Type 1 CD8α+ conventional dendritic cells (cDC1s) are required for CD8+ T cell priming but, paradoxically, promote splenic Listeria monocytogenes infection. Using mice with impaired cDC2 function, we ruled out a role for cDC2s in this process and instead discovered an interleukin-10 (IL-10)-dependent cellular crosstalk in the marginal zone (MZ) that promoted bacterial infection. Mice lacking the guanine nucleotide exchange factor DOCK8 or CD19 lost IL-10-producing MZ B cells and were resistant to Listeria. IL-10 increased intracellular Listeria in cDC1s indirectly by reducing inducible nitric oxide synthase expression early after infection and increasing intracellular Listeria in MZ metallophilic macrophages (MMMs). These MMMs trans-infected cDC1s, which, in turn, transported Listeria into the white pulp to prime CD8+ T cells. However, this also facilitated bacterial expansion. Therefore, IL-10-mediated crosstalk between B cells, macrophages, and cDC1s in the MZ promotes both Listeria infection and CD8+ T cell activation.
Subject(s)
B-Lymphocytes/immunology , Dendritic Cells/immunology , Interleukin-10/metabolism , Listeria monocytogenes/physiology , Listeriosis/immunology , Macrophages/immunology , Spleen/immunology , Animals , Antigens, CD19/metabolism , CD8 Antigens/metabolism , Cell Line, Tumor , Gene Expression Regulation , Guanine Nucleotide Exchange Factors/genetics , Interleukin-10/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Paracrine Communication , Spleen/microbiologyABSTRACT
Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.
Subject(s)
Arthritis , Behcet Syndrome , Biological Products , Inflammatory Bowel Diseases , Male , Humans , Behcet Syndrome/diagnosis , Behcet Syndrome/genetics , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/genetics , Arthralgia , DNA-Binding Proteins , Transcription Factors/geneticsABSTRACT
Anaphylaxis is a life-threatening allergic reaction caused by cross-linking of high-affinity IgE antibodies on the surface of mast cells and basophils. Understanding the cellular mechanisms that lead to high-affinity IgE production is required to develop better therapeutics for preventing this severe reaction. A recently discovered population of T follicular helper Tfh13 cells regulates the production of high-affinity IgE in mouse models of allergy and can also be found in patients with allergies with IgE antibodies against food or aeroallergens. Here we describe optimized protocols for identifying Tfh13 cells in both mice and humans.
Subject(s)
Cell Separation/methods , Flow Cytometry/methods , T Follicular Helper Cells , T-Lymphocyte Subsets , Animals , Humans , MiceABSTRACT
Podcasts have become increasingly popular tools for medical education in recent years. Only requiring a computer or smart phone, podcasts are readily accessible to healthcare professionals, helping to disseminate medical information quickly and creating a wide community of listeners. With numerous medical podcasts available and limited spare time, it can be challenging for a healthcare professional to identify the most high-yield podcast. This perspectives piece describes the role of podcasts in medical education before sharing five in-depth recommendations from Yale School of Nursing and Yale School of Medicine students and faculty. These five podcasts are: The Curbsiders Internal Medicine Podcast, Flip the Script, The Clinical Problem Solvers, 2 Docs Talk, and Key Literature in Medical Education (KeyLIME) Podcast. Each podcast summary includes its average length, the episode frequency, the intended audience, a brief description, a representative episode, and quotes from interviews with the podcast hosts.
Subject(s)
Education, Medical/methods , Webcasts as Topic , Humans , Students, Medical , Students, NursingABSTRACT
Differentiation of microbe-specific Tregs in the gut is directed by RORγt+ antigen-presenting cells.