42WTCd3e-/-The intersection of adaptive and innate immunity in the lung: implications for chronic pulmonary insufficiencyIn previous works, we demonstrated that the adaptive immune system plays critical roles in the maintenance of mucosal and systemic homeostasis by regulating the com-position and geographical distribution of gut microbiota (Fagarasan et al, Science 2002, Suzuki et al, PNAS 2004, Kawamoto et al, Science 2012, Kawamoto et al, Immunity 2014). More recently, we found that deficiency of even a single immune regulatory receptor, such as PD-1, leads to not only the breakdown of immune tolerance and gut barrier impairment and dysbiosis, but also that PD-1 deficiency impacts the biochemistry of the brain leading to behavioral changes (Miyajima et al, Nat. Immunol, 2017). We also noticed that T cell-deficient mice (Cd3e-/-), in addition to having dysbiosis, die younger than WT mice, for yet unknown reasons. These observations prompted us to ask wheth-er immunodeficiencies of the adaptive immune system impact other major physiological systems of the body.In addition to the gastrointestinal tract, the lung is a major mucosal tissue known to be affected by immunodeficiencies, and observations from patients with genetic im-mune defects, human immunodeficiency virus (HIV) or other viral infections revealed that pulmonary pathology is often the main cause of death. We found that around mid-dle age (6-7-months-old), T cell-deficient mice spontaneously develop collapsed lungs, characterized by pneumonia-like features, proteinosis and fibrosis (Figure). Thus, T cell-deficient mice might represent a useful mouse model for studying pulmonary pathogen-esis in immunodeficiencies associated with genetic defects or conditions such as aging.In this project, we characterized the cellular phenotypes and intercellular networks in the lung at a single-cell level in T cell-deficient mice and control wild-type mice at two different ages, before and at the peak of the lung inflammatory reaction, i.e., at 3 and 7 months of age, respectively. We further integrated the transcriptomic, metabolomic and proteomic profiles to understand how T cell deficiency disturbs pulmonary homeostasis.Our single-cell RNA sequencing analysis revealed considerable changes in the cellu-lar composition of the lung in T cell-deficient mice (Figure). Particularly, we identified early changes of the endothelial cells, indicating a shift from homeostatic to immune cell functions, such as decreased sealing capacity and increased antigen presenting features. We further identified changes in epithelial cells, myeloid cells and B cells present only in the Cd3e-/- mice, which may be linked to pulmonary alveolar proteinosis and fibrosis observed in the middle-aged mice.Metabolome analyses revealed several metabolites in the tryptophan-kynurenine pathway as significantly elevated in both bronchoalveolar lavage fluid (BALF) and lung tissues of Cd3e-/- mice. We also identified a B cell-derived metabolite, which we are cur-rently testing for its effect on the endothelial and myeloid cells in the lungs.Figure: HE staining and single-cell sequencing analysis showing a pneumonia-like pathology (left) and an altered cell composition of the lungs in T cell-deficient mice (right).Recent Major PublicationsAl-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Del-ghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Faga-rasan S*, Honjo T*. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science 378, eabj3510 (2022)*corresponding authorsChamoto K, Zhang B, Tajima M, Honjo T, Fagarasan S. Spermidine - an old molecule with a new age-defying immune function. Trends Cell Biol S0962-8924, 00166-6 (2023)Zhang B, Vogelzang A, Fagarasan S. Secreted immune metabolites that mediate immune cell communication and function. Trends Immunol 43, 990-1005 (2022)Macpherson AJ, Rolleske T, Kato L, Fagarasan S. 3Mu-cosal Immunity to bacteria and IgA synthesis. Book chapter. Molecular biology of B cells Textbook, Third edition.Invited presentationsFagarasan S. “The intersection of adaptive and innate immunity in the lung: implications for chronic pulmo-nary insufficiency” The 21th Awaji International Forum of Infection and Immunity (Nagano, Japan) September 2023Fagarasan S. “A novel B cell-derived metabolite inhibit-ing anti-tumor responses” RIKEN IMS-JSI International symposium in immunology (Tokyo, Japan) June 2023Fagarasan S. “On the biochemical dialog between major physiological systems mediates by immune cells” Global Immunotalk (Online) June 2023Fagarasan S. “Immunotherapy du Cancer. Secreted im-mune metabolites that mediate immune communica-tion and function” International Conference on Cancer Immunotherapy (Les Treilles, France) May 2023Fagarasan S. “A novel B cell-derived metabolite inhibit-ing anti-tumor immunity” The 81st Annual Meeting of the Japanese Cancer Association (Yokohama, Japan/Online) September 2022Laboratory for Mucosal ImmunityTeam Leader: Sidonia Fagarasan
元のページ ../index.html#48