Biology subjects

Gschwend, J.

Publications and source records attributed to Gschwend, J..

4 recordsLinked to original sources

bioRxiv2024

Sustained innate interferon is an essential inducer of tertiary lymphoid structures

Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in non-lymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages or CCL19 but crucially depends on type I (IFN-I)-but not type III interferon (IFN-III)-signaling. Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT) in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LT{beta}R-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LT{beta}R. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/591846v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@a2d940org.highwire.dtl.DTLVardef@165294aorg.highwire.dtl.DTLVardef@79c43forg.highwire.dtl.DTLVardef@4316ce_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

The tuft cell-ILC2 circuit orchestrates rapid type 2 responses upon detecting microbe-derived succinate and luminal helminths. Our findings delineate key mechanistic steps, involving IP3R2 engagement and Ca2+ flux, governing IL-25 production by tuft cells triggered by succinate detection. While IL-17RB plays a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Suboptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb-deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.

immunology↗

bioRxiv2021

Alveolar macrophages strictly rely on GM-CSF from alveolar epithelial type 2 cells before and after birth

Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and non-immune cells, and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular crosstalk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and {gamma}{delta} T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the non-redundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.

immunology↗

bioRxiv2020

Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and non-redundant action of two innate lymphocyte subpopulations, conventional NK cells (cNKs) and tissue-resident type I Innate Lymphoid Cells (trILC1s), is essential for anti-metastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 control metastatic seeding, whereas cNKs restrain outgrowth. The antimetastatic activity of cNKs is regulated in a tumor type-specific fashion. Thereby, individual cancer cell lines orchestrate the emergence of cNK subsets with unique phenotypic and functional traits. Understanding cancer-cell- as well as innate-cell-intrinsic factors will allow the exploitation of hepatic innate cells for development of novel cancer therapies. SignificanceInnate lymphoid cells hold great promise for the treatment of metastases. Development of effective therapies based on these versatile immune cells, however, is hampered by our limited knowledge of their behavior in the metastatic niche. Here, we describe that defense against liver metastasis requires the collaboration between two innate lymphocyte subsets, conventional NK cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s). We show that different cancers generate their own particular metastatic niche inducing specific changes in cNKs and trILC1s. Further, we uncover specific cNK subsets that can be manipulated to improve their anti-metastatic potential. Our work contributes to understanding how cancer-specific factors and hepatic innate lymphocytes exert mutual influence and how this can be exploited for therapeutic purposes. HighlightsO_LIcNKs and trILC1s collaborate to control hepatic metastasis C_LIO_LItrILC1s restrict seeding and cNKs control outgrowth of cancer cells in the liver C_LIO_LIIndividual cancer cell lines orchestrate a distinct metastatic niche C_LIO_LIThe metastatic niche dictates the phenotype and function of cNKs C_LI

immunology↗