title: STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model.
abstract: Donor CD4+ T cells are thought to be essential for inducing delayed host tissue injury in chronic graft-versus-host disease (GVHD). However, the relative contributions of distinct effector CD4+ T cell subpopulations and the molecular pathways influencing their generation are not known. We investigated the role of the STAT3 pathway in a murine model of chronic sclerodermatous GVHD. This pathway integrates multiple signaling events during the differentiation of naive CD4+ T cells and impacts their homeostasis. We report that chimeras receiving an allograft containing STAT3-ablated donor CD4+ T cells do not develop classic clinical and pathological manifestations of alloimmune tissue injury. Analysis of chimeras showed that abrogation of STAT3 signaling reduced the in vivo expansion of donor-derived CD4+ T cells and their accumulation in GVHD target tissues without abolishing antihost alloreactivity. STAT3 ablation did not significantly affect Th1 differentiation while enhancing CD4+CD25+Foxp3+ T cell reconstitution through thymus-dependent and -independent pathways. Transient depletion of CD25+ T cells in chimeras receiving STAT3-deficient T cells resulted in delayed development of alloimmune gut and liver injury. This delayed de novo GVHD was associated with the emergence of donor hematopoietic stem cell-derived Th1 and Th17 cells. These results suggest that STAT3 signaling in graft CD4+ T cells links the alloimmune tissue injury of donor graft T cells and the emergence of donor hematopoietic stem cell-derived pathogenic effector cells and that both populations contribute, albeit in different ways, to the genesis of chronic GVHD after allogenic bone marrow transplantation in a murine model.
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Vedran
authors.initials: V
authors.lastname: Radojcic
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pletneva
authors.forename: Hung-Rong
authors.initials: HR
authors.lastname: Yen
authors.forename: Sanja
authors.initials: S
authors.lastname: Ivcevic
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Anita C
authors.initials: AC
authors.lastname: Gilliam
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000209:etiology*; D051379:Mice; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000209:etiology*; D015398:Signal Transduction / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D050796:STAT3 Transcription Factor