CXCL16 blockade limits the persistence of asthmatic CD4 memory T cells in murine lungs 4391

Abstract Description The chemokine receptor CXCR6 is known to influence the CD8+ tissue-resident memory T (Trm) cells, but its role in CD4+ Trm remains unclear. Single-cell transcriptomic analyses of asthmatic lungs showed elevated CXCR6 expression on CD4+ T cells, aligned with single-cell RNA-seq data of allergen-reactive mouse CD4+ T cells. Confirming a role for CXCR6, short-term blockade of its ligand, CXCL16, during repeated allergen challenges reduced the accumulation of CD44hiCD62LloCD4+ lung memory effector cells by 50-60% consistent with decreased infiltration of immune cells into the bronchoalveolar lavage fluid (BALF) and lung tissue. This protective effect persisted with reduced numbers of lung CD4+ Trm being visualized over time, and was evident after subsequent allergen exposures, with a continued marked reduction in lung inflammation. Interestingly, blockade of chemokine signaling at late times after allergen exposure still resulted in fewer Trm being formed. This effect was reproduced by blocking antigen presentation with anti-MHC II, but not by inhibiting T cell trafficking into the lung with FTY720, highlighting the role of chemokine signaling in allowing continued antigen presentation within the lung and correlating with expression of CXCL16 in lung macrophages and dendritic cells. Together, our findings suggest that chemotactic blockade of CD4+ T cells regulates the allergen-reactive Trm cells accumulation and expansion, suggesting a potential therapeutic approach for asthma. Funding Sources This study was supported by Institutional funds from the La Jolla Institute for Immunology to Micheal Croft and the Tullie and Rickey Families SPARK Awards for Innovations in Immunology to Gurupreet Singh Sethi. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)