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

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. T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is a protein that has been associated with regulatory processes in different immune cells. Here the authors demonstrate that TIM-3 is associated with regulation of type 2 innate lymphoid cells (ILC2) and use two different mouse allergy models to show how signalling through TIM-3 reduces allergic responses and inflammation.