Biology subjects

von Moltke, J.

Publications and source records attributed to von Moltke, J..

6 recordsLinked to original sources

bioRxiv2025

Progenitor T cells drive chronic pulmonary type 2 inflammation

Type 2 inflammation unfolds over time and is coordinated by remarkably durable CD4+ Th2 cell responses, standing in contrast to the collapse of adaptive immunity seen in chronic infection and malignancy. In experimental models, short-lived Th2 effector cells and type 2 innate lymphocytes (ILC2) contribute to acute type 2 inflammation, yet the cellular architecture that drives chronic type 2 inflammation and prevents exhaustion remains poorly understood. To define the Th2 landscape in chronic type 2 inflammation, we established a mouse model of long-term pulmonary allergen exposure and found that type 2 inflammation was broadly sustained over at least 4 months despite chronic stimulation. Th2 cells in the lung parenchyma during chronic inflammation were distinct from acute inflammation and resting memory phases, and included an expanded T cell factor-1 (TCF1)-expressing progenitor-like Th2 population. Tissue Th2 progenitors were absent in the nose and in helminth infections, suggesting that type 2 immunopathology is context-specific. Transcriptomic deconstruction of acute and chronic pulmonary Th2 responses defined divergent effector programs as well as the transcriptional signature of a tissue Th2 memory population that resembled human Th2 progenitors. Integrated transcriptomic analysis comparing type 2 inflammation to chronic viral infection revealed a distinct stemness module underlying chronic Th2 inflammation that was separable from a common core memory module. In vivo, lung Th2 progenitors coupled self-renewal with effector cell differentiation and could be sustained for weeks without antigen persistence or contribution from the lymph node. Maintenance of Th2 progenitors was partially dependent on lung parenchymal B cells and associated with bronchus-associated lymphoid tissue formation. Moreover, Th2 progenitors, in contrast to Th2 effectors and ILC2s, were sufficient to both initiate and sustain type 2 inflammation. Thus, we define tissue Th2 progenitors as a distinct cellular state that arises during chronic type 2 inflammation and establish the central role of these cells in maintaining the architecture of Th2 responses over time.

immunology↗

bioRxiv2025

Tyrosine kinase inhibitors affect sweet taste and dysregulate fate selection of specific taste cell subtypes via KIT inhibition.

Taste dysfunction, or dysgeusia, is a common side effect of many cancer drugs. Dysgeusia is often reported by patients treated with anti-angiogenic tyrosine kinase inhibitors (TKIs), which inhibit receptor tyrosine kinases (RTKs). However, the mechanisms by which TKIs cause dysgeusia are not understood, as the role of RTKs in adult taste homeostasis is unknown. Here, we find that treating adult mice with the TKI cabozantinib shifts the fate of differentiating functional taste cell subtypes within taste buds. Through behavioral assays, we find this cell fate shift leads to blunted responses to sweet in cabozantinib-treated mice. Finally, we show that inducible knockout of the RTK KIT, which is inhibited by cabozantinib, phenocopies taste cell fate shifts induced by TKI treatment. Our results establish KIT as a regulator of taste cell homeostasis and suggest that KIT inhibition may underlie TKI-induced dysgeusia in patients. SummaryKIT signaling blockade by tyrosine kinase inhibitors alters the fate of functional taste bud cell subtypes.

neuroscience↗

bioRxiv2023

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. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.

immunology↗

bioRxiv2022

Genetic mapping reveals Pou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differential Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens. One Sentence SummaryGenetic mapping identifies Pou2af2 isoform usage as a novel regulator of tuft cell differentiation that tunes intestinal innate type 2 immunity.

immunology↗

bioRxiv2021

Direct reprogramming of the intestinal epithelium by parasitic helminths subverts type 2 immunity

Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the symbiotic parasite Heligmosomoides polygyrus bakeri (Hbp), reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory/secretory products reveal that Hpb-mediated revSC generation occurs independent of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness indicating that helminths compete with their host for control of the intestinal stem cell niche to promote continuation of their life cycle.

immunology↗

bioRxiv2018

Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

Initiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis secretes succinate as a metabolite, and sensing of both succinate and N. brasiliensis requires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

immunology↗