Takataro Fukuhara: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Yoshihiro Ueda: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan. ORCID
Sung-Il Lee: Department of Model Animal, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Tokifumi Odaka: Department of Microbiology, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Shinsuke Nakajima: Department of Microbiology, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Jun-Ichi Fujisawa: Department of Microbiology, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Kazu Okuma: Department of Microbiology, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Makoto Naganuma: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Kazuichi Okazaki: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Naoyuki Kondo: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan. ORCID
Yuji Kamioka: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan. ORCID
Mitsuru Matsumoto: Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Kuramoto 770-8503, Tokushima, Japan.
Tatsuo Kinashi: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan.
Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via the intra-bone marrow injection of CD133+ cord blood cells into irradiated adult immunodeficient mice (IBMI-huNSG mice), which could mount functional immune responses against HTLV-1, although the underlying mechanisms were still unknown. Here, we investigated thymocyte development in IBMI-huNSG mice, focusing on the roles of human and mouse MHC restriction. IBMI-huNSG mice had normal developmental profiles but aberrant thymic structures. Surprisingly, the thymic medulla-like regions expanded after immunization due to enhanced thymocyte expansion in association with the increase in HLA-DR+ cells, including CD205 dendritic cells (DCs). The organ culture of thymus from immunized IBMI-huNSG mice with a neutralizing antibody to HLA-DR showed the HLA-DR-dependent expansion of CD4 single positive thymocytes. Mature peripheral T-cells exhibited alloreactive proliferation when co-cultured with human peripheral blood mononuclear cells. Live imaging of the thymus from immunized IBMI-huNSG mice revealed dynamic adhesive contacts of human-derived thymocytes and DCs accompanied by Rap1 activation. These findings demonstrate that an increase in HLA-DR+ cells by immunization promotes HLA-restricted thymocyte expansion in humanized mice, offering a unique opportunity to generate humanized mice with ease.
20K17036/Japan Society for the Promotion of Science
a cooperative research grant from the Institute for Enzyme Research Joint Usage/Research Center/Tokushima University
a "Private University Research Branding Project on intractable immune and allergic diseases" grant from Kansai Medical University/Kansai Medical University
