The responsiveness of ILC2s in allergic airway inflammation

Allergic airway disease is one of the leading health problems in the USA and the world, and there are only limited treatment and prevention methods. A better understanding of the pathogenesis remains critical for developing efficacious treatment. Studies have shown that immune infiltrates, especially T helper (TH) 2 cells, play crucial roles in pathogenesis. In addition to TH2 cells, group 2 innate lymphoid cells (ILC2s) are an important driving force of allergic responses, which is, at least in part, by promoting TH2 cell development. Therefore, restriction of the responsiveness of ILC2s may achieve a therapeutic purpose. Despite many studies on the induction and functional promotion of ILC2s, there is little understanding of the negative regulation of these cells, which can be one of the directions to manipulate them. The proposed studies will address this knowledge gap and elucidate the mechanisms underlying the counter-regulation of allergic airway inflammation via regulating the responsiveness of ILC2s. Our previous studies have identified the cytokine signal suppressor Cytokine Induced SH2 protein (CIS or CISH) as a key regulator that negatively controls TH2 (and TH9) responses and inhibits allergic airway inflammation. Mice deficient in Cis spontaneously develop chronic airway inflammation during aging, resembling human adult- onset allergic asthma; however, mice with T cell-specific Cis-deficiency do not develop a similar disease, suggesting that additional cell types other than T cells with Cis-deficiency play a critical role in the development of the spontaneous disease. Recently, Kotas et al. demonstrated that CIS constrains intestinal ILC2 responses. In line with this, we showed that CIS restricts pulmonary ILC2 responses (preliminary results). Although lacking mechanistic insight, the above observations lay the groundwork for our current research. The current proposal will address a novel hypothesis that CIS serves as an essential checkpoint in ILC2s to restrict pro-allergic TH cell differentiation, leading to the suppression of allergic airway disease. Project Number: 1R01HL175382-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Xuexian Yang | Institution: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR, ALBUQUERQUE, NM | Award Amount: $522,990 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IMHA-B (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17538201A1