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

in Immunity by 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

TLDR

  • The study reveals the critical role of Delta-like1 (Dll1) Notch ligands in regulating splenic marginal zone B (MZB) cell pool size, migration, and function.
  • The findings highlight the importance of the Notch signaling pathway in regulating MZB cell function and provide insights into the potential therapeutic targeting of this pathway for treating diseases characterized by MZB cell dysfunction.

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.

Overview

  • The study investigates the rapid responsiveness of splenic marginal zone B (MZB) cells to blood-borne microbes and how they integrate cell-extrinsic and intrinsic processes to achieve this.
  • The researchers found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulate MZB cell pool size, migration, and function.
  • The primary objective of the study is to understand how MZB cells integrate cell-extrinsic and intrinsic processes to achieve accelerated responsiveness, and how this process is regulated by the Notch signaling pathway.

Comparative Analysis & Findings

  • The study shows that Dll1, but not the alternative Notch ligand Dll4, regulates MZB cell pool size, migration, and function.
  • Dll1-Notch2 signaling regulates 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).
  • The study also found that S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation.

Implications and Future Directions

  • The study highlights the importance of the Notch signaling pathway in regulating the pool size, migration, and function of MZB cells.
  • The study suggests that the development of therapies targeting Notch signaling could be a potential approach for treating diseases characterized by dysfunction of MZB cells.
  • Future studies could investigate the conservation of these findings in other immune cell types and the potential implications for human diseases.
Read Full Article