1: Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus
Science of the Month - February 2022
Hisato Iriki, Hayato Takahashi, Naoko Wada, Hisashi Nomura, Miho Mukai, Aki Kamata, Hiromi Ito, Jun Yamagami, Takeshi Matsui, Yutaka Kurebayashi, Setsuko Mise-Omata, Hiroshi Nishimasu, Osamu Nureki, Akihiko Yoshimura, Shohei Hori, and Masayuki Amagai
Peripheral immune tolerance is a crucial mechanism for preventing autoimmunity, but many aspects remain unclear. In this study, we focused on desmoglein 3 (Dsg3), the target antigen in the autoimmune blistering disease pemphigus. We transplanted thymuses from Dsg3-deficient mice into athymic mice, creating a condition where Dsg3 is not expressed in the thymus but only in peripheral tissues, thus eliminating the influence of thymic tolerance to Dsg3. Dsg3-specific CD4-positive (H1) T cells differentiated in the transplanted thymus but were eliminated in peripheral tissues. Furthermore, when H1 T cells differentiated in the absence of Dsg3 were transferred into wild-type mice, they were eliminated in an antigen-specific and regulatory T cell (Treg)-dependent manner. In co-culture experiments, Tregs used OX40 to capture OX40L from dendritic cells. Conversely, in Treg-specific OX40-deficient mice, OX40L expression on dendritic cells increased, and the OX40 signal in transferred H1 T cells was enhanced, allowing them to evade elimination. In conclusion, we have elucidated a peripheral immune tolerance mechanism whereby Tregs suppress the OX40 signal in autoreactive T cells, leading to their elimination.
(Hisato Iriki, Class of 90, Department of Dermatology)
2: Epithelium Replacement Contributes to Field Expansion of Squamous Epithelium and Ulcerative Colitis-Associated Neoplasia.
Gastroenterology.
2022; 162: 334–337.e5. doi: 10.1053/j.gastro.2021.09.051.
Sugimoto S, Iwao Y, Shimoda M, Takabayashi K, Sato T, Kanai T; Keio IBD Collaborators
In the process of tissue regeneration, epithelial cells adjacent to an injury contribute to mucosal healing by covering the damaged area. In this study, we incidentally observed a phenomenon where the rectum, which should normally be lined with simple columnar epithelium, underwent squamous metaplasia when the colonic epithelium of mice was mechanically injured. We determined that if the injury is contiguous with the anus, it can be repaired by stratified squamous epithelium originating from the anus. Therefore, we hypothesized that a similar phenomenon could occur in human diseases involving chronic inflammation of the colon and verified this using clinical data from ulcerative colitis-associated neoplasia, which is known to form fields. We found that tumors formed at the transition zone between the squamous epithelium extending from the anus and the columnar epithelium. We also confirmed cases where post-endoscopic treatment ulcers were repaired by the adjacent squamous epithelium. This study not only reveals a new clinical significance for a previously overlooked biological phenomenon in ulcerative colitis but also clinically demonstrates that the human colon can be regenerated by different types of epithelial cells.
(Shinya Sugimoto, Class of 88, The Sakaguchi Laboratory (Organoid Medicine) / Gastroenterology)
Other Published Papers
1: Parallel-Group Controlled Trial of Surgery Versus Chemoradiotherapy in Patients With Stage I Esophageal Squamous Cell Carcinoma.
Gastroenterology.
2021 Dec;161(6):1878-1886.e2. doi: 10.1053/j.gastro.2021.08.007.
Kato K, Ito Y, Nozaki I, Daiko H, Kojima T, Yano M, Ueno M, Nakagawa S, Takagi M, Tsunoda S, Abe T, Nakamura T, Okada M, Toh Y, Shibuya Y, Yamamoto S, Katayama H, Nakamura K, Kitagawa Y.
2: Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments.
Hepatology.
Kurebayashi Y, Matsuda K, Ueno A, Tsujikawa H, Yamazaki K, Masugi Y, Kwa WT, Effendi K, Hasegawa Y, Yagi H, Abe Y, Kitago M, Ojima H, Sakamoto M.