IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease

Caisheng Lu; Huihui Ma; Liangsong Song; Hui Wang; Lily Wang; Shirong Li; Stephen M. Lagana; Antonia R. Sepulveda; Kasper Hoebe; Samuel S. Pan; Yong-Guang Yang; Suzanne Lentzsch; Markus Y. Mapara

doi:10.1172/JCI125986

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Lu, C. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Ma, H. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Song, L. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Wang, L. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Li, S. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Lagana, S. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Sepulveda, A. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Hoebe, K. in: JCI | PubMed | Google Scholar |

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Pan, S. in: JCI | PubMed | Google Scholar |

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Yang, Y. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Lentzsch, S. in: JCI | PubMed | Google Scholar

¹Columbia Center for Translational Immunology, Columbia University, New York, United States of America

²Division of Hematology/Oncology, Columbia University, New York, United States of America

³Department of Pathology and Cell Biology, Columbia University, New York, United States of America

⁴Department of Pathology and Cell Biology, George Washington University, Washington DC, United States of America

⁵Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, United States of America

⁶Cancer Biostatistics Shared Resource, Herbert Irving Columbia Cancer Center, New York, United States of America

⁷Columbia University, New York, United States of America

Find articles by Mapara, M. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI125986.
Copyright © 2022, Lu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published November 29, 2022 - Version history

Absence of Interferon-γ Receptor (IFNGR) or Signal Transducer and Activator of Transcription 1 (STAT1) signaling in donor cells has been shown to result in reduced acute GVHD induction. In this study, we unexpectedly observed increased activation and expansion of donor lymphocytes in both lymphohematopoietic organs and GVHD target tissues of IFNGR/STAT1-deficient recipient mice, leading to rapid mortality following the induction of GVHD. Lipopolysaccharide (LPS)-matured bone marrow-derived Ifngr1^-/-/Stat1^-/-dendritic cells (BMDCs) were more potent allogeneic stimulators and expressed increased levels of MHC II and costimulatory molecules. Similar effects were observed in human APCs with knockdown of Stat1 by CRISPR/Cas9 and treatment with a JAK1/2 inhibitor. Furthermore, we demonstrated that the absence of IFNGR/STAT1 signaling in hematopoietic APCs impaired the presentation of exogenous antigens while promoting the presentation of endogenous antigens. In contrast, the indirect presentation of host antigens to donor lymphocytes was defective in IFNGR/STAT1-deficient donor-derived APCs in fully donor chimeric mice. The differential effects of IFNGR/STAT1 signaling on endogenous and exogenous antigen presentation could provide further insight into the roles of the IFN-γ/STAT1 signal pathway in the pathogenesis of GVHD, organ rejection, and autoimmune diseases.

Version 1 (November 29, 2022): In-Press Preview

IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease

Caisheng Lu,¹ Huihui Ma,¹ Liangsong Song,¹ Hui Wang,¹ Lily Wang,¹ Shirong Li,² Stephen M. Lagana,³ Antonia R. Sepulveda,⁴ Kasper Hoebe,⁵ Samuel S. Pan,⁶ Yong-Guang Yang,⁷ Suzanne Lentzsch,² and Markus Y. Mapara¹

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IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease

Caisheng Lu,1 Huihui Ma,1 Liangsong Song,1 Hui Wang,1 Lily Wang,1 Shirong Li,2 Stephen M. Lagana,3 Antonia R. Sepulveda,4 Kasper Hoebe,5 Samuel S. Pan,6 Yong-Guang Yang,7 Suzanne Lentzsch,2 and Markus Y. Mapara1

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Caisheng Lu,¹ Huihui Ma,¹ Liangsong Song,¹ Hui Wang,¹ Lily Wang,¹ Shirong Li,² Stephen M. Lagana,³ Antonia R. Sepulveda,⁴ Kasper Hoebe,⁵ Samuel S. Pan,⁶ Yong-Guang Yang,⁷ Suzanne Lentzsch,² and Markus Y. Mapara¹