Basic Fibroblast Growth Factor 2 Is a Determinant of CD4 T Cell–Airway Smooth Muscle Cell Communication through Membrane Conduits

Abstract

Activated CD4 T cells connect to airway smooth muscle cells (ASMCs) in vitro via lymphocyte-derived membrane conduits (LMCs) structurally similar to membrane nanotubes with unknown intercellular signals triggering their formation. We examined the structure and function of CD4 T cell-derived LMCs, and we established a role for ASMC-derived basic fibroblast growth factor 2 (FGF2b) and FGF receptor (FGFR)1 in LMC formation. Blocking FGF2b's synthesis and FGFR1 function reduced LMC formation. Mitochondrial flux from ASMCs to T cells was partially FGF2b and FGFR1 dependent. LMC formation by CD4 T cells and mitochondrial transfer from ASMCs was increased in the presence of asthmatic ASMCs that expressed more mRNA for FGF2b compared with normal ASMCs. These observations identify ASMC-derived FGF2b as a factor needed for LMC formation by CD4 T cells, affecting intercellular communication.

FGF2, an Immunomodulatory Factor in Asthma and Chronic Obstructive Pulmonary Disease (COPD)

“…Except for this, FGF2 also plays a role in the contact-dependent communication between immune cells and ASMCs, which is featured in chronic airway diseases and being critical for ASM functional changes and immune cell survival (Ramos- Barbon et al, 2005). In this scenario, FGF2/FGFR signaling in ASMCs is thought to trigger the formation of lymphocyte-derived membrane conduits, which are a continuum of cell membrane extensions and connect ASMCs and activated CD4 + T cells (Farahnak et al, 2017).…”

CD4+ T cell‐derived IFN‐γ and LIGHT synergistically upregulate chemokine production from airway smooth muscle cells

“…A wide array of cell surface interactions, such as integrin adhesion molecules, CD44 hyaluronan, and costimulatory molecules CD40 and CD86, mediate T cell adherence, ASM cell proliferation, and reciprocal activation of the two cell types 8,12 . Furthermore, activated CD4 + T cells extend membrane protrusions, termed lymphocyte‐derived membrane conduits (LMCs), to ASM cells, whose formation is dependent on basic fibroblast growth factor 2 (FGF2b) signaling through the FGF receptor (FGFR)‐1 13,14 . LMCs facilitate the transfer of anti‐apoptotic proteins immunoreactive B cell lymphoma 2 (Bcl‐2) and induced myeloid leukemia cell differentiation protein (Mcl‐1), as well as ASM‐derived mitochondria to promote CD4+ T cell survival 13,14 …”

“…Furthermore, activated CD4 + T cells extend membrane protrusions, termed lymphocyte‐derived membrane conduits (LMCs), to ASM cells, whose formation is dependent on basic fibroblast growth factor 2 (FGF2b) signaling through the FGF receptor (FGFR)‐1 13,14 . LMCs facilitate the transfer of anti‐apoptotic proteins immunoreactive B cell lymphoma 2 (Bcl‐2) and induced myeloid leukemia cell differentiation protein (Mcl‐1), as well as ASM‐derived mitochondria to promote CD4+ T cell survival 13,14 …”

“…8,12 Furthermore, activated CD4 + T cells extend membrane protrusions, termed lymphocytederived membrane conduits (LMCs), to ASM cells, whose formation is dependent on basic fibroblast growth factor 2 (FGF2b) signaling through the FGF receptor (FGFR)-1. 13,14 LMCs facilitate the transfer of anti-apoptotic proteins immunoreactive B cell lymphoma 2 (Bcl-2) and induced myeloid leukemia cell differentiation protein (Mcl-1), as well as ASM-derived mitochondria to promote CD4+ T cell survival. 13,14 The tumor necrosis factor (TNF) family ligand LIGHT (TNFSF14; lymphotoxin exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator (HVEM), a receptor expressed on T lymphocytes) is a cytokine expressed by several immune cell types, including activated T cells, B cells, and macrophages.…”

The small molecule fibroblast growth factor receptor inhibitor infigratinib exerts anti‐inflammatory effects and remyelination in a model of multiple sclerosis

“…Furthermore, FGF2 levels in the cerebrospinal fluid are higher in MS patients, with the highest expression found in relapse (Sarchielli et al, 2008). FGFRs are also expressed in immune cells, notably FGFR1 is found in CD4 + T cells of healthy subjects (Farahnak et al, 2017). In lupus nephritis, FGFR1 is expressed in infiltrating lymphocytes and macrophages (Rossini et al, 2005).…”