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

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: dallman@pennmedicine.upenn.edu.
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: maillai@mskcc.org.

PMID: 39731910
PMCID: PMC11735314 (available on 2026-01-14)
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

Anneka Allman et al. Immunity. 2025.

. 2025 Jan 14;58(1):143-161.e8.

doi: 10.1016/j.immuni.2024.12.003. Epub 2024 Dec 27.

Authors

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: dallman@pennmedicine.upenn.edu.
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: maillai@mskcc.org.

PMID: 39731910
PMCID: PMC11735314 (available on 2026-01-14)
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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests S.K. is currently employed by Century Therapeutics; L.C. by Interius BioTherapeutics; D.G.A. by Aro Biotherapeutics; and C.W.S by Gilead Sciences. L.M. is a current and C.W.S. a former employee of Genentech. I.M. has received research funding from Genentech and Regeneron and is a member of Garuda Therapeutics’s scientific advisory board.

References

1. Martin F, Oliver AM, and Kearney JF (2001). Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629. - PubMed
1. Oliver AM, Martin F, and Kearney JF (1999). IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J Immunol 162, 7198–7207. - PubMed
1. Oliver AM, Martin F, Gartland GL, Carter RH, and Kearney JF (1997). Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur J Immunol 27, 2366–2374. 10.1002/eji.1830270935. - DOI - PubMed
1. Gaudette BT, Roman CJ, Ochoa TA, Gomez Atria D, Jones DD, Siebel CW, Maillard I, and Allman D (2021). Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation. J Clin Invest 131. 10.1172/JCI151975. - DOI - PMC - PubMed
1. Gaudette BT, Jones DD, Bortnick A, Argon Y, and Allman D (2020). mTORC1 coordinates an immediate unfolded protein response-related transcriptome in activated B cells preceding antibody secretion. Nat Commun 11, 723. 10.1038/s41467-019-14032-1. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous