title: CD8+T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure.
abstract: Bone marrow (BM) failure syndrome encompasses a group of disorders characterized by BM stem cell dysfunction, resulting in varying degrees of hypoplasia and blood pancytopenia, and in many patients is autoimmune and inflammatory in nature. The important role of T helper 1 (Th1) polarized CD4+T cells in driving BM failure has been clearly established in several models. However, animal model data demonstrating a functional role for CD8+T cells in BM dysfunction is largely lacking and our objective was to test the hypothesis that CD8+T cells play a non-redundant role in driving BM failure. Clinical evidence implicates a detrimental role for CD8+T cells in BM failure and a beneficial role for Foxp3+regulatory T cells (Tregs) in maintaining immune tolerance in the BM. We demonstrate that IL-2-deficient mice, which have a deficit in functional Tregs, develop spontaneous BM failure. Furthermore, we demonstrate a critical role for CD8+T cells in the development of BM failure, which is dependent on the cytokine, IFNγ. CD8+T cells promote hematopoietic stem cell dysfunction and depletion of myeloid lineage progenitor cells, resulting in anemia. Adoptive transfer experiments demonstrate that CD8+T cells dramatically expedite disease progression and promote CD4+T cell accumulation in the BM. Thus, BM dysregulation in IL-2-deficient mice is mediated by a Th1 and IFNγ-producing CD8+T cell (Tc1) response.
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Gravano
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
authors.forename: Mufadhal
authors.initials: M
authors.lastname: Al-Kuhlani
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Davini
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
authors.forename: P Dominick
authors.initials: PD
authors.lastname: Sanders
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA; Health Sciences Research Institute, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Manilay
authors.affiliation: Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA; Health Sciences Research Institute, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA. Electronic address: khoyer2@ucmerced.edu.
authors.forename: Katrina K
authors.initials: KK
authors.lastname: Hoyer
mesh_terms: D019264:Adoptive Transfer; D000740:Anemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D007371:Interferon-gamma
keywords: Autoimmune; Bone marrow failure; Hematopoietic stem cell; Interferon gamma; Interleukin-2; T cells