Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine.

Tuft cell-derived acetylcholine regulates epithelial fluid secretion.

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown.

Initiation of type 2 immunity at barrier surfaces.

Although seemingly unrelated, parasitic worms, venoms, and allergens all induce a type 2 immune response. The effector functions and clinical features of type 2 immunity are well-defined, but fundamental questions about the initiation of type 2 immunity remain unresolved. How are these enormously diverse type 2 stimuli first detected? How are type 2 helper T cells primed and regulated? And how do mechanisms of type 2 initiation vary across tissues? Here, we review the common themes governing type 2 immune sensing and explore aspects of T cell priming and effector reactivation that make type 2 helper T cells a unique T helper lineage.

Effector memory CD4 T cells induce damaging innate inflammation and autoimmune pathology by engaging CD40 and TNFR on myeloid cells.

Cytokine storm and sterile inflammation are common features of T cell-mediated autoimmune diseases and T cell-targeted cancer immunotherapies. Although blocking individual cytokines can mitigate some pathology, the upstream mechanisms governing overabundant innate inflammatory cytokine production remain unknown. Here, we have identified a critical signaling node that is engaged by effector memory T cells (T) to mobilize a broad proinflammatory program in the innate immune system.

Innate control of adaptive immunity and adaptive instruction of innate immunity: bi-directional flow of information.

The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations.

IRF1 governs the differential interferon-stimulated gene responses in human monocytes and macrophages by regulating chromatin accessibility.

Myeloid lineage cells use TLRs to recognize and respond to diverse microbial ligands. Although unique transcription factors dictate the outcome of specific TLR signaling, whether lineage-specific differences exist to further modulate the quality of TLR-induced inflammation remains unclear. Comprehensive analysis of global gene transcription in human monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells stimulated with various TLR ligands identifies multiple lineage-specific, TLR-responsive gene programs.

TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation.

Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined.

Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs Is Critical for T Cell Priming.

Inflammasome activation leads to pyroptotic cell death, thereby eliminating the replicative niche of virulent pathogens. Although inflammasome-associated cytokines IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we find that conventional DCs (cDCs) suppress inflammasome activation to prevent pyroptotic cell death, thus preserving their ability to prime both CD4 and CD8 T cells.

T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity.

The cytokine interleukin (IL)-1β is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1β requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1β production seen in T cell-driven autoimmune diseases remains unclear.

Modelling Bovine Granuloma Formation In Vitro upon Infection with Subspecies .

subspecies () causes chronic granulomatous disease in cattle and ruminant livestock, causing substantial economic losses. Current vaccines delay clinical signs but cannot train the immune system to fully eradicate latent . During latency, uses host defenses, cage-like macrophage clusters called granuloma, as incubators for months or years.

Estimating Residence Times of Lymphocytes in Ovine Lymph Nodes.

The ability of lymphocytes to recirculate between blood and secondary lymphoid tissues such as lymph nodes (LNs) and spleen is well established. Sheep have been used as an experimental system to study lymphocyte recirculation for decades and multiple studies document accumulation and loss of intravenously (i.v.

Severe Gut Microbiota Dysbiosis Is Associated With Poor Growth in Patients With Short Bowel Syndrome.

Background: Children with short bowel syndrome (SBS) can vary significantly in their growth trajectory. Recent data have shown that children with SBS possess a unique gut microbiota signature compared with healthy controls. We hypothesized that children with SBS and poor growth would exhibit more severe gut microbiota dysbiosis compared with those with SBS who are growing adequately, despite similar intestinal anatomy.

Quantifying Limits on Replication, Death, and Quiescence of Mycobacterium tuberculosis in Mice.

When an individual is exposed to Mycobacterium tuberculosis (Mtb) three outcomes are possible: bacterial clearance, active disease, or latent infection. It is generally believed that most individuals exposed to Mtb become latently infected and carry the mycobacteria for life. How Mtb is maintained during this latent infection remains largely unknown.