Tissue-resident memory T (TRM) cells are a unique subset of T cells that 35permanently reside in various peripheral tissues and play dominant roles in protective immunity at barrier surfaces. TRM cells also contribute to cancer immunity, autoimmunity, allergy, and inflammatory disease, and are therefore major candidates for vaccine development and immunotherapy. However, how TRM cells are maintained in different peripheral tissues and tumors remains poorly understood.The use of mouse models of influenza virus infection with experimental approaches such as intravenous antibody staining and parabiosis have allowed us to precisely identify lung resident TRM subsets. With this methodology, we have discovered that CD8+ TRM cells in the lung are generated and maintained in transient niches created at sites of tissue damage and regeneration, and that these CD8+ TRM cells are maintained independently of tissue-circulating effec-tor memory T cells (TEM). Interestingly, however, our study also demonstrated that lung resident CD8+ TRM cells display a relatively shorter lifespan than TRM cells in other tissues, which is due to the loss of these transient niches during tissue repair. Nevertheless, we have recently identified a specific CD8+ TRM sub-population that is selectively maintained in the lung following infection, raising the possibility that the preferential generation of this unique TRM subset may prolong their longevity, as well as promoting TRM-mediated protection against rechallenge. Thus, we are now investigating the mechanisms that drive the generation of this unique and long-lived CD8+ TRM population upon influenza infection, which could greatly improve protocols for vaccine engineering.Furthermore, studies from cancer patients have recently revealed that some tumors, especially those of epithelial origin, harbor CD8+ T cells with TRM char-acteristics (TRM-like TILs). High frequencies of these intra-tumoral TRM-like TILs are highly associated with improved responses to tumor immunotherapy and have favorable clinical outcomes for cancer patients. Hence, increasing the numbers of TRM-like TILs is a promising approach to clinically improve the effects of immunotherapy. Unfortunately, current mouse models have yet to report the existence of murine TRM-like TILs, therefore limiting our ability to identify mechanisms that drive TRM-like TIL development. To overcome this obstacle, we used human-derived cancer specimens and immunohistochemis-try to identify tumoral sites for TRM-like TIL generation. Presently, we are using spatial transcriptomics to elucidate the molecular processes required for TRM-like TIL development.Figure: Localization of CD8+ TRM cells and TRM-like TIL in barrier and tumoral tissues(A) Congenic host mice (CD90.1+) were infected i.n. with influenza virus and were subjected to parabiotic surgery with partner mice (CD90.2+) at 22 days post-infection. Parabionts were analyzed on day 14 post-surgery. The image shows the distributions of CD103+ host-derived (CD90.1+) TRM cells inside or outside of peribronchiolar foci. (B) Tumor specimens from cancer patients with head and neck cancer were subjected to immunohisto-chemistry. The image shows the distribution of TRM-like TILs (CD103+ CD8+ double positive) versus CD8+ single positive T cells.Recent Major PublicationsTakamura S, Nomura A, Kubo M. BCL6 fine-tune long-term tumor control. Sci Immunol 8, eadj6724 (2023)Miyagawa C, Nakai H, Otani H, Murakami R, Takamura S, Takaya H, Murakami K, Mandai M, Matsumura N. His-topathological subtyping of high-grade serous ovarian cancer using whole slide imaging. J Gynecol Oncol 34, e47 (2023)Kawasaki T, Ikegawa M, Yunoki K, Otani H, Ori D, Ishii KJ, Kuroda E, Takamura S, Kitabatake M, Ito T, Isotani A, Kawai T. Alveolar macrophages instruct CD8+ T cell ex-pansion by antigen cross-presentation in lung. Cell Rep 41, 111828 (2022)Invited presentationsTakamura S. “Long-term maintenance of tissue-resident memory CD8+ T cells in the lung” Kanazawa Univer-sity Sakigake Symposium, Immunological Memory. (Kanazawa, Japan) January 2024Takamura S. “Generation and maintenance of epithelial-tropic CD8+ T cells in the peripheral tissues and tumor” Kobe University Special Lecture in Global Medical Sci-ence (Kobe, Japan) December 2023Takamura S. “Generation and maintenance of epithelial-tropic CD8+ T cells in the peripheral tissues and tumor” The 19th Primate Medical Science Forum (Tsukuba, Japan) November 2023Laboratory for Immunological MemoryTeam Leader: Shiki Takamura
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