title: Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD.
abstract: Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. Transplantation of STAT1(-/-) bone marrow (BM) prevented GVHD induced by STAT1(+/+) T cells, leading to expansion of B220(+) cells and regulatory T cells. STAT1(-/-) BM also preserved GVT activity and enhanced overall survival of tumor-challenged mice in the setting of GVHD. Furthermore, recipients of allogeneic STAT1(-/-) BM demonstrated increased CD9(-)Siglec H(hi) plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1(-/-) BM transplantation prevented GVHD resistance. STAT1(-/-) pDCs were found to produce decreased free radicals, IFNα, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1(-/-) pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9(-/-) BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1(-/-) pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis.
authors: Department of Pediatrics and Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI;
authors: Christian M
authors: http://orcid.org/0000-0002-2276-6731
authors: CM
authors: Capitini
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Nicole M
authors: NM
authors: Nasholm
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Christopher D
authors: CD
authors: Chien
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Shannon M
authors: SM
authors: Larabee
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Haiying
authors: H
authors: Qin
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Young K
authors: YK
authors: Song
authors: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors: Peter J
authors: PJ
authors: Klover
authors: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors: Lothar
authors: L
authors: Hennighausen
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Javed
authors: J
authors: Khan
authors: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Terry J
authors: TJ
authors: Fry
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D040501:Calgranulin A / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse