title: CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia.
abstract: Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (αIIbβ3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTLs) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Because steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, whereas CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tregs while decreasing CTLs. In vitro coculture studies revealed CD8(+) Tregs suppressed CD4(+) and CD19(+) proliferation, platelet-associated immunoglobulin G generation, CTL cytotoxicity, platelet apoptosis, and clearance. Furthermore, we found increased production of anti-inflammatory interleukin-10 in coculture studies and in vivo after steroid treatment. Thus, we uncovered subsets of CD8(+) Tregs and demonstrated their potent immunosuppressive and protective roles in experimentally induced thrombocytopenia. The data further elucidate mechanisms of steroid treatment and suggest therapeutic potential for CD8(+) Tregs in immune thrombocytopenia.
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada;
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;
authors.forename: Elisa
authors.initials: E
authors.lastname: Simpson
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Min
authors.initials: M
authors.lastname: Xuan
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada;
authors.forename: Laura
authors.initials: L
authors.lastname: Baker
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Haematology, Qilu Hospital, Shandong University, Jinan, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada;
authors.forename: Issaka
authors.initials: I
authors.lastname: Yougbaré
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; The Second Affiliated Hospital of Nanchang University, Jiangxi, China; and.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada;
authors.forename: Guangheng
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada;
authors.forename: Pingguo
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine and.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Lazarus
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine and.
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine and Department of Physiology, University of Toronto, ON, Canada.
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D003131:Combined Modality Therapy; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016219:Immunotherapy, Adoptive; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic; D016896:Treatment Outcome
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D003907:Dexamethasone