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

Abstract

AbstractAirway smooth muscle (ASM) remodeling in asthmatic airways may contribute to persistent airflow limitation and airway hyperresponsiveness. CD4+ T cells infiltrate the ASM layer where they may induce a proliferative and secretory ASM cell phenotype. We studied the interaction between activated CD4+ T cells and ASM cells in co‐culture in vitro and investigated the effects of CD4+ T cells on chemokine production by ASM cells. CD4+ T cells induced marked upregulation of C‐X‐C motif chemokine ligands (CXCL) 9, 10, and 11 in ASM cells. Blockade of the IFN‐γ receptor on ASM cells prevented this upregulation. Furthermore, T cell‐derived IFN‐γ and LIGHT (lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) synergize in a dose‐dependent manner to coordinately enhance CXCL9, 10, and 11 expression. The synergistic property of LIGHT was mediated exclusively through the lymphotoxin‐β receptor (LTBR), but not herpes virus entry mediator (HVEM). Disruption of LTBR signaling in ASM cells reduced CXCL9, 10, and 11 production and ASM cell‐mediated CD4+ T cell chemotaxis. We conclude that the LIGHT‐LTBR signaling axis acts together with IFN‐γ to regulate chemokines that mediate lymphocyte infiltration in asthmatics.