[R01] Study the role of ICOS on murine and human ILC2s
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2030-05-31
Importo max: 590.670 EUR
Paese: US
Descrizione
SUMMARY
The long-term goal of this study is to increase our understanding of the immune mechanisms involved in the
pathogenesis of allergic diseases and asthma. Allergic asthma is a chronic inflammatory disorder that is
characterized by airway hyperreactivity (AHR) and driven by Th2 cytokine production. Group 2 innate lymphoid
cells (ILC2s) secrete high amounts of Th2 cytokines and contribute to the development of AHR. This project is
motivated by our published results (Maazi et al., Immunity), demonstrating that ICOS is extensively used by
activated ILC2s to maintain their homeostasis and effector functions. We originally discovered that the lack of
ICOS resulted in decreased proinflammatory cytokine secretion contributing to a reduced induction of AHR in
models of experimental ILC2-driven asthma and ILC2-humanized mice. However, recently, we discovered that
these effects are associated with a phenotypical change characterized by IL-10 secretion. Our preliminary results
suggest that this regulatory gain of function associated with ICOS predominantly occurs via a metabolic
reprogramming of ILC2s. From current evidence and preliminary data, we hypothesize that modulation of ICOS
on ILC2s will reprogram ILC2 metabolism and induce an anti-inflammatory phenotype capable of regulating
ILC2-dependent AHR. Importantly, our laboratory and others have reported that ILC2s are the only cells that
express both ICOS and corresponding ligand ICOS-L. We therefore leveraged ICOS:ICOS-L bispecific blocking
antibody-based strategies to selectively reduce ILC2-derived type-2 cytokine secretion while also promoting that
of IL-10, without affecting the function of other ICOS-expressing cells. In Specific Aim 1, we intend to determine
the necessity of specific transcription factors in IL-10 production in ILC2s. Moreover, we will investigate the role
of ICOS on DNA methylation of the il10 locus through modulation of the Tet3 pathway. Since the lack of ICOS
dysregulates metabolic checkpoints signaling and gives rise to augmented glycolysis, in Specific Aim 2 we
intend to assess the role of ICOS on ILC2 metabolism. We will examine the capacity of targeted combinatorial
metabolic and functional interventions to reprogram ILC2s and induce a regulatory phenotype. We will
investigate the effects of ICOS inhibition on mitochondrial health, function and its relation to ILC2 activation.
Finally, in Specific Aim 3 we intend to focus on the translational approach of our findings by investigating the
role of ICOS on human ILC2s in a cohort of well-defined patients with allergic asthma at USC. We will investigate
whether selective blockage of ICOS: ICOS-L axis on human ILC2s can ameliorate AHR in humanized mice
without affecting the function of other ICOS-expressing human cells such as Tregs in vivo. To conduct these
studies, we have assembled a team of scientists including leading experts in costimulatory molecules and a
clinical pulmonology team at USC to complement our laborator
Istituzione: UNIVERSITY OF SOUTHERN CALIFORNIA
PI: OMID AKBARI
Progetto: 5R01AI181866-02
Settori: National Institute of Allergy and Infectious Diseases
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