Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

• Published in: Scientific reports 2019-10, Vol.9 (1), p.14955-10, Article 14955
• Main Authors: Fischer, Julius C., Bscheider, Michael, Göttert, Sascha, Thiele Orberg, Erik, Combs, Stephanie E., Bassermann, Florian, Heidegger, Simon, Haas, Tobias, Poeck, Hendrik
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/31; 631/250/1904; 64/60; 692/308/2778; 96/2; Animal models; Animals; Bone Marrow Transplantation; CD11c antigen; CD11c Antigen - metabolism; Cell activation; Cell Death; Cell Proliferation; Graft vs Host Disease; Graft-versus-host reaction; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humanities and Social Sciences; Immunoregulation; Immunosuppression; Interferon; Interferon Type I - metabolism; Irradiation; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Radiation; Science; Science (multidisciplinary); Signal Transduction; Stem cell transplantation; Stem cells; T-Lymphocytes - cytology; Transplantation Conditioning; Transplantation, Homologous
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51431-2

Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c + recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c + recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.