MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model

• Published in: eLife 2016-01, Vol.5, p.e09394-e09394
• Main Authors: Ogawa, Yoko, Morikawa, Satoru, Okano, Hideyuki, Mabuchi, Yo, Suzuki, Sadafumi, Yaguchi, Tomonori, Sato, Yukio, Mukai, Shin, Yaguchi, Saori, Inaba, Takaaki, Okamoto, Shinichiro, Kawakami, Yutaka, Tsubota, Kazuo, Matsuzaki, Yumi, Shimmura, Shigeto
• Format: Article
• Language: English
• Subjects: Adipocytes; adoptive transfer; Animals; Antigens; auto-reactive T cells; Autoimmune diseases; autoimmune response/disease; Bone marrow; Bone Marrow - pathology; Bone marrow transplantation; Bone Marrow Transplantation - adverse effects; CD25 antigen; Developmental Biology and Stem Cells; Disease; Disease Models, Animal; dry eye disease; Effector cells; Fibroblasts; Fibrosis; Fibrosis - pathology; Foxp3 protein; Genetic aspects; Health aspects; Immunology; Interleukin 6; Lymphocytes T; Major histocompatibility complex; Medicine; mesenchymal stem cell; Mice; Pathogenesis; Population; RAG2 protein; Rodents; Scleroderma; Scleroderma, Diffuse - pathology; Stem cell transplantation; Stem cells; Stem Cells - immunology; Stromal Cells - immunology; Syngeneic grafts; T cells; T-Lymphocytes - immunology; Transplantation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.09394

Fibrosis of organs is observed in systemic autoimmune disease. Using a scleroderma mouse, we show that transplantation of MHC compatible, minor antigen mismatched bone marrow stromal/stem cells (BMSCs) play a role in the pathogenesis of fibrosis. Removal of donor BMSCs rescued mice from disease. Freshly isolated PDGFRα(+) Sca-1(+) BMSCs expressed MHC class II following transplantation and activated host T cells. A decrease in FOXP3(+) CD25(+) Treg population was observed. T cells proliferated and secreted IL-6 when stimulated with mismatched BMSCs in vitro. Donor T cells were not involved in fibrosis because transplanting T cell-deficient RAG2 knock out mice bone marrow still caused disease. Once initially triggered by mismatched BMSCs, the autoimmune phenotype was not donor BMSC dependent as the phenotype was observed after effector T cells were adoptively transferred into naïve syngeneic mice. Our data suggest that minor antigen mismatched BMSCs trigger systemic fibrosis in this autoimmune scleroderma model.