CXCL16 as a potential therapeutic target to limit the activity of asthmatic CD4 memory T cells.

Abstract

The C-X-C motif chemokine receptor CXCR6 is considered a marker of some tissue-resident memory T (Trm) cells, but its importance in controlling lung CD4 Trm cells in asthma remains unclear. We explored the involvement of CXCL16-CXCR6 interactions in the activity and accumulation of CD4 Trm cells relevant to lung inflammatory disease. Human and murine asthmatic lung CD4 T cells were analyzed by single-cell transcriptomics to assess CXCR6 expression, and the effects of blocking the CXCL16-CXCR6 pathway were then evaluated using a disease model. Single-cell RNA sequencing of human and murine asthmatic lung cells revealed elevated CXCR6 mRNA expression in CD4 T cells. Confirming a role for CXCR6, short-term blockade of its ligand, CXCL16, during repeated intranasal allergen challenges in the mouse reduced the accumulation of lung CD4 memory effector T cells by 50% to 70%, coincident with decreased tissue inflammation. This protective effect persisted, with reduced numbers of lung CD4 Trm cells being visualized over time, and was evident during subsequent asthma exacerbations shown by a tolerogenic effect with continued marked reduction in lung inflammation. Late blockade of CXCL16 after allergen exposure also resulted in fewer Trm cells, an effect reproduced by blocking antigen presentation but not by inhibiting T-cell trafficking into the lung. This implies a role of the chemokine in sustaining local antigen presentation and correlates with CXCL16 expression being found in human asthmatic lung macrophages, monocytes, and dendritic cells. CXCL16 blockade may regulate allergen-induced CD4 Trm cell accumulation and persistence in the lungs, suggesting a potential therapeutic approach for asthma.