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 STAT11/1 T cells, leading to expansion of B2201 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-/-BMdemonstrated increased CD92Siglec Hhi plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1-/-BM transplantation prevented GVHD resistance. STAT1-/-pDCs were found to produce decreased free radicals, IFNa, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1-/-pDCs that were isolated after alloBMT showed increased gene expressionof S100A8 and S100A9, and transplantation of S100A92/2 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.