Tim-3 Agonist Restrains ILC2 Function and Attenuates Airway Hyperreactivity via NLK Pathway
Allergic asthma is driven 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 was upregulated in activated pulmonary ILC2s, and engagement with Tim-3 agonists inhibited ILC2 activation, proliferation, and type 2 cytokine production via the NLK signaling pathway and suppression of mitochondrial metabolism. In vivo, Tim-3 agonists alleviated airway hyperreactivity (AHR) and inflammation in both IL-33- and Alternaria alternata-induced AHR models, while ILC2-specific Tim-3 deletion exacerbated AHR. These results were 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. Overall design: mRNA profiles of mouse lung ILC2s which were cultured with isotype control or Tim3 agonist,  from CB57BL/6 mice were generated by deep sequencing, in duplicates, using a NextSeq 500.