Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs

Anneka Allman; Brian T Gaudette; Samantha Kelly; Nagham Alouche; Léolène J Carrington; Eric Perkey; Joshua D Brandstadter; Riley Outen; Ashley Vanderbeck; Katlyn Lederer; Yeqiao Zhou; Robert B Faryabi; Tanner F Robertson; Janis K Burkhardt; Anastasia Tikhonova; Iannis Aifantis; Leonardo Scarpellino; Ute Koch; Freddy Radtke; Mechthild Lütge; Angelina De Martin; Burkhard Ludewig; Lena Tveriakhina; Achim Gossler; Lluc Mosteiro; Christian W Siebel; Daniela Gómez Atria; Sanjiv A Luther; David Allman; Ivan Maillard

doi:10.1016/j.immuni.2024.12.003

Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs

Immunity. 2024 Dec 25:S1074-7613(24)00567-3. doi: 10.1016/j.immuni.2024.12.003. Online ahead of print.

Authors

Anneka Allman¹, Brian T Gaudette², Samantha Kelly¹, Nagham Alouche³, Léolène J Carrington¹, Eric Perkey⁴, Joshua D Brandstadter¹, Riley Outen¹, Ashley Vanderbeck⁵, Katlyn Lederer⁵, Yeqiao Zhou², Robert B Faryabi², Tanner F Robertson⁶, Janis K Burkhardt⁷, Anastasia Tikhonova⁸, Iannis Aifantis⁹, Leonardo Scarpellino³, Ute Koch¹⁰, Freddy Radtke¹⁰, Mechthild Lütge¹¹, Angelina De Martin¹¹, Burkhard Ludewig¹¹, Lena Tveriakhina¹², Achim Gossler¹², Lluc Mosteiro¹³, Christian W Siebel¹³, Daniela Gómez Atria¹, Sanjiv A Luther³, David Allman¹⁴, Ivan Maillard¹⁵

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
⁴ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
⁵ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁹ Department of Pathology, New York University School of Medicine, New York, NY, USA.
¹⁰ EPFL, Lausanne, Switzerland.
¹¹ Medical Research Center, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹² Institute for Molecular Biology, Medizinische Hochschule, Hannover, Germany.
¹³ Genentech, South San Francisco, CA, USA.
¹⁴ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].
¹⁵ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].

PMID: 39731910
DOI: 10.1016/j.immuni.2024.12.003

Abstract

Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function. Dll1 could not be replaced by the alternative Notch ligand Dll4. Dll1-Notch2 signaling regulated a Myc-dependent gene expression program fostering cell growth and a Myc-independent program controlling cell-movement regulators such as sphingosine-1 phosphate receptor 1 (S1PR1). S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation. Key elements of the mouse B cell Notch regulome were preserved in subsets of human memory B cells and B cell lymphomas. Thus, specialized niches program the poised state and patrolling behavior of MZB cells via conserved Myc-dependent and Myc-independent Notch2-regulated mechanisms.

Keywords: B cells; Notch; chemotaxis; fibroblastic reticular cells; marginal zone; spleen.