1. CD8 + T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure.
- Author
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Gravano DM, Al-Kuhlani M, Davini D, Sanders PD, Manilay JO, and Hoyer KK
- Subjects
- Adoptive Transfer, Anemia genetics, Anemia immunology, Anemia metabolism, Animals, Bone Marrow metabolism, Bone Marrow pathology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Flow Cytometry, Forkhead Transcription Factors, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukin-2 deficiency, Interleukin-2 genetics, Interleukin-2 immunology, Mice, Inbred BALB C, Mice, Knockout, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Autoimmunity immunology, Bone Marrow immunology, Bone Marrow Cells immunology, CD8-Positive T-Lymphocytes immunology, Hematopoietic Stem Cells immunology
- 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., Competing Interests: Disclosures: The authors have declared that no conflict of interest exists., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2016
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