Interferon‐γ amplifies airway smooth muscle‐mediated CD4+ T cell recruitment by promoting the secretion of C–X–C‐motif chemokine receptor 3 ligands

Asthmatic airways feature increased ASM mass that is largely attributable to hyperplasia, and which potentially contributes to excessive airway narrowing. T cells induce ASMC proliferation via contact‐dependent mechanisms in vitro that may have importance for asthmatic ASM growth, as CD4+ T cells infiltrate ASM bundles in asthmatic human airways. In this study, we used an in vitro migration assay to investigate the pathways responsible for the trafficking of human CD4+ T cells to ASM. ASMCs induced chemotaxis of activated CD4+ T cells, which was inhibited by the CXCR3 antagonist AMG487 and neutralizing antibodies against its ligands CXCL10 and 11, but not CCR3 or CCR5 antagonists. CXCR3 expression was upregulated among all T cells following anti‐CD3/CD28‐activation. CD4+ T cells upregulated CXCL9, 10, and 11 expression in ASMCs in an IFN‐γ/STAT1‐dependent manner. Disruption of IFN‐γ‐signaling resulted in reduced T cell migration, along with the inhibition of CD4+ T cell‐mediated STAT1 activation and CXCR3 ligand secretion by ASMCs. ASMCs derived from healthy and asthmatic donors demonstrated similar T cell‐recruiting capacities. In vivo CXCL10 and 11 expression by asthmatic ASM was confirmed by immunostaining. We conclude that the CXCL10/11‐CXCR3 axis causes CD4+ T cell recruitment to ASM that is amplified by T cell‐derived IFN‐γ.