title: Bridging channel dendritic cells induce immunity to transfused red blood cells.
abstract: Red blood cell (RBC) transfusion is a life-saving therapeutic tool. However, a major complication in transfusion recipients is the generation of antibodies against non-ABO alloantigens on donor RBCs, potentially resulting in hemolysis and renal failure. Long-lived antibody responses typically require CD4(+) T cell help and, in murine transfusion models, alloimmunization requires a spleen. Yet, it is not known how RBC-derived antigens are presented to naive T cells in the spleen. We sought to answer whether splenic dendritic cells (DCs) were essential for T cell priming to RBC alloantigens. Transient deletion of conventional DCs at the time of transfusion or splenic DC preactivation before RBC transfusion abrogated T and B cell responses to allogeneic RBCs, even though transfused RBCs persisted in the circulation for weeks. Although all splenic DCs phagocytosed RBCs and activated RBC-specific CD4(+) T cells in vitro, only bridging channel 33D1(+) DCs were required for alloimmunization in vivo. In contrast, deletion of XCR1(+)CD8(+) DCs did not alter the immune response to RBCs. Our work suggests that blocking the function of one DC subset during a narrow window of time during RBC transfusion could potentially prevent the detrimental immune response that occurs in patients who require lifelong RBC transfusion support.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Samuele
authors.initials: S
authors.lastname: Calabro
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gallman
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Uthaman
authors.initials: U
authors.lastname: Gowthaman
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Yuexiu, Guangzhou, Guangdong, 510080, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jayendra Kumar
authors.initials: JK
authors.lastname: Krishnaswamy
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Manuela Sales L
authors.initials: MS
authors.lastname: Nascimento
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030.
authors.forename: Adam
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Tormey
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center-New York Presbyterian Hospital, New York, NY 10032.
authors.forename: Eldad A
authors.initials: EA
authors.lastname: Hod
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center-New York Presbyterian Hospital, New York, NY 10032.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Spitalnik
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, WA 98102 Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98102 Division of Hematology, Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA 98102.
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
authors.affiliation: Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Stowell
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 stephanie.eisenbarth@yale.edu.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology*; D017707:Erythrocyte Transfusion; D005700:Galactosyltransferases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000017:ABO Blood-Group System; C427751:Abo protein, mouse; D005700:Galactosyltransferases