Biology subjects

Nitschke, L.

Publications and source records attributed to Nitschke, L..

5 recordsLinked to original sources

bioRxiv2026

B-cell SIGLEC-5 engages T-cell components of the elastin receptor complex (ERC) to suppress inflammatory T-cell cytokines

SIGLECs remain poorly defined in human B-cell biology beyond SIGLEC-2/CD22 and SIGLEC-10. Here, we identify a previously unrecognized regulatory pathway involving the paired receptors SIGLEC-5 and SIGLEC-14 at the human B-T-cell interface. We show that activated B-cells differentially regulate these receptors: SIGLEC-5 is predominantly surface-expressed and induced by CD40 engagement, whereas SIGLEC-14 is primarily secreted and upregulated after both CD40 and TLR9 stimulation. We further identify EBP (elastin binding protein) and CTSA (cathepsin A) components of the elastin receptor complex (ERC), expressed by activated T-cells, as a novel ligand for both SIGLEC-5 and SIGLEC-14. Functionally, ERC-associated engagement of SIGLEC-5 on B-cells suppresses T-cell IFN-{gamma} and IL-17 expression, establishing SIGLEC-5 as a B-cell-expressed inhibitory SIGLEC that restrains inflammatory T-cell cytokine responses. SIGLEC-14 does not alter this suppression, as SIGLEC-5{square} B-cells from SIGLEC-14-sufficient and -null individuals show comparable inhibitory activity. These findings broaden SIGLEC-mediated adaptive immune regulation, with relevance to inflammatory and autoimmune disease.

immunology↗

bioRxiv2021

TWIST1 interacts with adherens junction proteins during neural tube formation and regulates fate transition in cranial neural crest cells

Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate embryos and emerge from the neural fold borders into multiple cell lineages that differentiate into bone, cartilage, neurons, and glial cells. We previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicates that TWIST1 interacts with /{beta}/{gamma}-CATENINS during neural tube closure, and Irf6 is involved in the structural integrity of the neural tube. Twist1 suppresses Irf6 and other epithelial genes in CNCCs during epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs. Disruption of TWIST1 phosphorylation in vivo leads to epidermal blebbing, edema, neural tube defects, and CNCC-derived structural abnormalities. Altogether, this study describes an uncharacterized function of Twist1 and Irf6 in the neural tube and CNCCs and provides new target genes of Twist1 involved in cytoskeletal remodeling. Furthermore, the association between DNA variations within TWIST1 putative enhancers and human facial morphology is also investigated. SUMMARY STATEMENTThis study uncovers a new function of Twist1 in neural tube development and epithelial-to-mesenchymal transition in cranial neural crest cells. Data further shows that Twist1-interacting Irf6 is involved in regulating neural tube integrity.

developmental biology↗

bioRxiv2021

Coordinated changes in glycosylation regulate the germinal centre through CD22

Germinal centres (GC) are sites of B-cell expansion and selection, which are essential for antibody affinity maturation. Compared to naive follicular B-cells, GC B-cells have several notable changes in their cell surface glycans. While these changes are routinely used to identify the GC, functional roles for these changes have yet to be ascribed. Detection of GCs by the antibody GL7 reflects a reduction in the glycan ligands for CD22, which is an inhibitory co-receptor of the B-cell receptor (BCR). To test a functional role for downregulated CD22 ligands in the GC, we generated a mouse model that maintains CD22 ligands on GC B-cells. With this model, we demonstrate that glycan remodeling is crucial for proper GC B-cell response, including plasma cell output and affinity maturation of antibodies. The defect we observe in this model is dependent on CD22, highlighting that coordinated downregulation of CD22 ligands on B cells plays a critical function in the GC. Collectively, our study uncovers a crucial role for glycan remodeling and CD22 in B-cell fitness in the GC.

immunology↗

bioRxiv2020

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression.

The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin {beta}7, but not for {beta}1 or {beta}2 integrins. Viable motheaten mice deficient for SHP-1 have less {beta}7 on T cells and lack {beta}7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in {beta}7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses {beta}7 endocytosis: internalization of {beta}7 but not {beta}1 integrin is accelerated in SHP-1+/- and CD22-/- B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce 4{beta}7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control {beta}7 expression. Integrin 4{beta}7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/- B cells display reduced {beta}7-dependent homing to gut associated Peyers patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin {beta}7-specific role for CD22-SHP-1 interplay in mucosal immunity.

immunology↗

bioRxiv2019

Intravital quantification of absolute cytoplasmic B cell calcium reveals dynamic signaling across B cell differentiation stages

Development, function and maintenance of lymphocytes largely depend upon the cellular mobilization and storage of Ca2+ ions. In B lymphocytes, the absolute amount of calcium mobilized and retained after cell signaling remains unknown, athough it is a crucial part of their selection within germinal centers and differentiation into plasma cells. Here, we introduce the novel reporter mouse strain YellowCaB that expresses the genetically encoded calcium indicator TN-XXL in CD19+ lymphocytes. The construct consists of the electrondonor fluorophore eCFP and the acceptor citrine, linked by a calcium sensitive domain. Its conformation and therefore donor quenching is directly linked to cytosolic calcium concentrations. By combining intravital two-photon fluorescence lifetime microscopy with our numerical approach for phasor-based analysis, we are able to extract absolute cytoplasmic calcium concentrations in activated B cells for the first time in vivo. We show that calcium concentrations in B cells are highly dynamic and fluctuations persist in extrafollicular B cells with functional relevance.

immunology↗