CXCL16作为限制哮喘性CD4记忆T细胞活性的潜在治疗靶点
2026/06/01
摘要
背景：趋化因子受体CXCR6被认为是某些组织驻留记忆T细胞（Trm）的标志物，但其在控制哮喘肺部CD4 Trm中的重要性尚不明确。
目的：探讨CXCL16-CXCR6相互作用在与肺部炎症性疾病相关的CD4 Trm活性和积累中的作用。
方法： 采用单细胞转录组学技术分析人类和小鼠哮喘模型肺部的CD4 T细胞，评估CXCR6的表达水平，并在疾病模型中进一步评估阻断CXCL16-CXCR6通路的效应。
结果：对人及小鼠哮喘模型肺部细胞的单细胞RNA测序显示，CD4T细胞中CXCR6的mRNA表达水平升高。为验证CXCR6的作用，在小鼠反复经鼻吸入过敏原激发过程中短期阻断其配体CXCL16，结果肺部CD4记忆效应T细胞的积累减少了50%-70%，同时组织炎症减轻。这种保护效应具有持续性，随时间推移观察到肺部CD4 Trm数量持续减少，并且在后续的哮喘急性加重中仍然显著，表现为一种耐受诱导效应，肺部炎症持续显著减轻。在过敏原暴露后晚期阻断CXCL16同样导致Trm数量减少，这一效应可通过阻断抗原呈递来复制，但通过抑制T细胞向肺部的迁移则无法实现。这表明该趋化因子在维持局部抗原呈递中发挥作用，并与人类哮喘肺部巨噬细胞、单核细胞和树突状细胞中CXCL16的表达相一致。
结论： 阻断CXCL16可能调节过敏原诱导的肺部CD4 Trm的积累和持续存在，提示了一种潜在的哮喘治疗方法。
CXCL16 as a Potential Therapeutic Target to Limit the Activity of Asthmatic CD4 Memory T cells.
Gurupreet S, Sethi; Michael, CroftAbstrast
BACKGROUND: The chemokine receptor CXCR6 is considered a marker of some tissue-resident memory T cells (Trm) but its importance in controlling lung CD4 Trm in asthma remains unclear.
OBJECTIVE: To explore the involvement of CXCL16-CXCR6 interactions in the activity and accumulation of CD4 Trm relevant to lung inflammatory disease.
METHODS: Human and murine asthmatic lung CD4 T cells were analyzed using single-cell transcriptomics to assess CXCR6 expression and the effects of blocking the CXCL16-CXCR6 pathway were then evaluated using a disease model.
RESULTS: scRNA-seq 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 50-70% coincident with decreased tissue inflammation. This protective effect persisted, with reduced numbers of lung CD4 Trm 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, 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.
CONCLUSION: CXCL16 blockade may regulate allergen-induced CD4 Trm accumulation and persistence in the lungs, suggesting a potential therapeutic approach for asthma.
背景：趋化因子受体CXCR6被认为是某些组织驻留记忆T细胞（Trm）的标志物，但其在控制哮喘肺部CD4 Trm中的重要性尚不明确。
目的：探讨CXCL16-CXCR6相互作用在与肺部炎症性疾病相关的CD4 Trm活性和积累中的作用。
方法： 采用单细胞转录组学技术分析人类和小鼠哮喘模型肺部的CD4 T细胞，评估CXCR6的表达水平，并在疾病模型中进一步评估阻断CXCL16-CXCR6通路的效应。
结果：对人及小鼠哮喘模型肺部细胞的单细胞RNA测序显示，CD4T细胞中CXCR6的mRNA表达水平升高。为验证CXCR6的作用，在小鼠反复经鼻吸入过敏原激发过程中短期阻断其配体CXCL16，结果肺部CD4记忆效应T细胞的积累减少了50%-70%，同时组织炎症减轻。这种保护效应具有持续性，随时间推移观察到肺部CD4 Trm数量持续减少，并且在后续的哮喘急性加重中仍然显著，表现为一种耐受诱导效应，肺部炎症持续显著减轻。在过敏原暴露后晚期阻断CXCL16同样导致Trm数量减少，这一效应可通过阻断抗原呈递来复制，但通过抑制T细胞向肺部的迁移则无法实现。这表明该趋化因子在维持局部抗原呈递中发挥作用，并与人类哮喘肺部巨噬细胞、单核细胞和树突状细胞中CXCL16的表达相一致。
结论： 阻断CXCL16可能调节过敏原诱导的肺部CD4 Trm的积累和持续存在，提示了一种潜在的哮喘治疗方法。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（J Allergy Clin Immunol 2026 May 13;(0). DOI:10.1016/j.jaci.2026.05.004. IF: 10.228）
（J Allergy Clin Immunol 2026 May 13;(0). DOI:10.1016/j.jaci.2026.05.004. IF: 10.228）
CXCL16 as a Potential Therapeutic Target to Limit the Activity of Asthmatic CD4 Memory T cells.
Gurupreet S, Sethi; Michael, CroftAbstrast
BACKGROUND: The chemokine receptor CXCR6 is considered a marker of some tissue-resident memory T cells (Trm) but its importance in controlling lung CD4 Trm in asthma remains unclear.
OBJECTIVE: To explore the involvement of CXCL16-CXCR6 interactions in the activity and accumulation of CD4 Trm relevant to lung inflammatory disease.
METHODS: Human and murine asthmatic lung CD4 T cells were analyzed using single-cell transcriptomics to assess CXCR6 expression and the effects of blocking the CXCL16-CXCR6 pathway were then evaluated using a disease model.
RESULTS: scRNA-seq 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 50-70% coincident with decreased tissue inflammation. This protective effect persisted, with reduced numbers of lung CD4 Trm 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, 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.
CONCLUSION: CXCL16 blockade may regulate allergen-induced CD4 Trm accumulation and persistence in the lungs, suggesting a potential therapeutic approach for asthma.
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