Biology subjects

Zimber-Strobl, U.

Publications and source records attributed to Zimber-Strobl, U..

4 recordsLinked to original sources

bioRxiv2022

Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation

Notch2 signaling has a profound role in driving the development of Marginal Zone B (MZB) cells. We recently demonstrated that Follicular B (FoB) cells act as precursors for MZB cells in mice, but the mechanistic aspects of this differentiation pathway are still elusive. By studying Notch signaling in CBF:H2B-Venus Notch-reporter mice, we show that most B cells receive a Notch signal, which is highest in MZB cells. However, surprisingly, around one-third of MZB cells seem to lose their Notch signal with time. Conditional deletion or constitutive activation of Notch2 in mice upon T-cell-dependent (TD) immunization unraveled an interplay between antigen-induced activation and Notch2 signaling, in which FoB cells that turn off the Notch pathway enter germinal centers, whereas FoB cells with high Notch signals undergo MZB cell or plasmablast differentiation. Input of experimental data into a mathematical modeling framework reveals that MZB cells regularly emerge from antigen-activated FoB cells in a Notch2-dependent manner upon TD immunization.

immunology↗

bioRxiv2018

Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma.

Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-{kappa}B. The pre-clinical L.CD40 transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-{kappa}B continuous activation with a spleen monoclonal B-cell tumor after one year in 60% of cases. L.CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-{kappa}B, JAK1/JAK2 or BTK pathways since ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of L.CD40 lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.

cancer biology↗

bioRxiv2018

Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice.

Transformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.\n\nSummary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

cancer biology↗

bioRxiv2018

Jagged1/Notch2 Controls Kidney Fibrosis via Tfam-mediated Metabolic Reprogramming

While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined.\n\nIn this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome wide expression analysis of a large cohort of human kidney samples. RNA sequencing analysis of kidneys of mice with folic acid nephropathy, unilateral ureteral obstruction, or APOL1-associated kidney disease indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox, and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline, but showed protection from folic acid induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knock-out of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Kidney tubule specific deletion of Tfam resulted in perinatal lethality.\n\nIn summary, Jag1/Notch2 plays a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.

pathology↗