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<p>Allergic asthma is promoted by type 2 inflammation involving cytokines such as IL-4, IL-5, and IL-13, with group 2 innate lymphoid cells (ILC2s) playing a key pathogenic role. Here, we identify T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) as a negative regulator of ILC2 function. Tim-3 expression is upregulated in activated pulmonary ILC2s, and engagement with Tim-3 agonists inhibits ILC2 activation, proliferation, and type 2 cytokine production via the Nemo Like Kinase (NLK) signaling pathway and suppression of mitochondrial metabolism. In vivo, Tim-3 agonists alleviate airway hyperreactivity (AHR) and inflammation in both IL-33- and <i>Alternaria alternata</i>-induced AHR models, while ILC2-specific Tim-3 deletion exacerbates AHR. These results are confirmed in human ILC2s and humanized mice, supporting the translational relevance. Our findings establish Tim-3 as an inhibitory checkpoint for ILC2s and suggest its potential as a therapeutic target in allergic asthma and other ILC2-mediated diseases.</p>

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Tim-3 agonist restrains ILC2 function and attenuates airway hyperreactivity via NLK pathway

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月1日

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  • Yoshihiro Sakano,
  • Kei Sakano,
  • Kota Kokubo,
  • Benjamin P. Hurrell,
  • Stephen Shen,
  • Xin Li,
  • Gowri Yeliyur Shivakumara Swamy,
  • Jafar Cain,
  • Vijay K. Kuchroo,
  • Omid Akbari

摘要

Allergic asthma is promoted by type 2 inflammation involving cytokines such as IL-4, IL-5, and IL-13, with group 2 innate lymphoid cells (ILC2s) playing a key pathogenic role. Here, we identify T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) as a negative regulator of ILC2 function. Tim-3 expression is upregulated in activated pulmonary ILC2s, and engagement with Tim-3 agonists inhibits ILC2 activation, proliferation, and type 2 cytokine production via the Nemo Like Kinase (NLK) signaling pathway and suppression of mitochondrial metabolism. In vivo, Tim-3 agonists alleviate airway hyperreactivity (AHR) and inflammation in both IL-33- and Alternaria alternata-induced AHR models, while ILC2-specific Tim-3 deletion exacerbates AHR. These results are confirmed in human ILC2s and humanized mice, supporting the translational relevance. Our findings establish Tim-3 as an inhibitory checkpoint for ILC2s and suggest its potential as a therapeutic target in allergic asthma and other ILC2-mediated diseases.