IgE産生細胞で特異的な細胞凝集を介した抗体産生増加のメカニズム

application/pdf本研究は、これまでに試験管内で見出してきたI型アレルギー疾患に関与するIgE産生細胞が抗原と抗体、IgG受容体FcgRを介して細胞凝集を引き起こす機構を詳細に解明すること、そして生体内のどういった組織に局在するIgE産生細胞が凝集するかを明らかにすることを目的とした。その結果、IgE産生細胞は様々な組織に局在すること、そして凝集は脾臓のみで観察されることを明らかにした。また、生体内の抗体産生細胞でFcgRIIIの発現が観察され、生体内でのIgE産生細胞の凝集に関与する可能性を示した。IgE producing cells are related to type I hypersensitivity, but little is known about the specific phenotype of IgE producing cells. we focused on the cell aggregation of IgE-producing cells via antigen-IgE bound FcgRII/FcgRIII. This cell aggregation was observed only in IgE-producing cells by using IgE-producing cell line. Here, we examined where IgE-producing cells aggregated and whether these cells expressed FcgRII/FcgRIII in vivo. We showed that IgE-producing cells are present in spleen, mesenteric lymph node and thymus of antigen/alum-administrated mice, but the cell aggregation was found only in spleen. Furthermore, we found the expression of FcgRIII on antibody poruding cells. In this study, we obtained the new finding about the phenotype of IgE producing cells.2017年度～2018年度科学研究費補助金(研究活動スタート支援)研究成果報告書著者「國石茉里」の報告書での表記は「 國石茉里(彦坂)」17H0676

Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins