IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

Blood. 2017 May 4;129(18):2507-2518. doi: 10.1182/blood-2016-08-737239. Epub 2017 Feb 15.


Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by the accumulation of germinal center-derived malignant B cells engaged in a bidirectional crosstalk with their supportive microenvironment in invaded lymph nodes (LNs) and bone marrow (BM). T follicular helper (TFH) cells and infiltrating stromal cells have been shown to favor FL B-cell growth, but the mechanisms of their protumoral effect and how the LN/BM microenvironment is converted into a lymphoma-permissive cell niche remain poorly understood. We demonstrated here that FL-infiltrating LN and BM stromal cells overexpressed CXCL12 in situ. Interleukin-4 high (IL-4hi) FL-TFH cells, unlike FL B cells themselves, triggered CXCL12 upregulation in human stromal cell precursors. In agreement, expression of CXCL12 was associated with IL-4 expression and signaling within the FL BM and LN niches. This IL-4/CXCL12 axis was amplified in activated lymphoid stromal cells as shown in our in vitro model of human lymphoid stroma differentiation and in an inducible mouse model of ectopic lymphoid organ formation. Finally, CXCL12 triggered primary FL B-cell activation, migration, and adhesion, a process antagonized by BTK and PI3K inhibitors. These data identified the IL-4/CXCL12 loop as a previously unrecognized pathway involved in lymphoid stroma polarization and as a potential therapeutic target in FL patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Bone Marrow / immunology*
  • Bone Marrow / pathology
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / immunology*
  • Female
  • Humans
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Lymph Nodes / immunology*
  • Lymph Nodes / pathology
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / immunology*
  • Lymphoma, Follicular / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Stromal Cells / immunology
  • Stromal Cells / pathology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • IL4 protein, human
  • Interleukin-4