Gravano David M, Al-Kuhlani Mufadhal, Davini Dan, Sanders P Dominick, Manilay Jennifer O, Hoyer Katrina K
Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, 5200 N. Lake Rd., Merced, CA 95343, USA.
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.
J Autoimmun. 2016 Dec;75:58-67. doi: 10.1016/j.jaut.2016.07.007. Epub 2016 Jul 21.
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.
骨髓（BM）衰竭综合征包括一组以BM干细胞功能障碍为特征的疾病，导致不同程度的发育不全和全血细胞减少，并且在许多患者中本质上是自身免疫性和炎症性的。在多个模型中已明确证实辅助性T细胞1（Th1）极化的CD4 T细胞在驱动BM衰竭中起重要作用。然而，很大程度上缺乏动物模型数据来证明CD8 T细胞在BM功能障碍中的功能作用，我们的目的是检验CD8 T细胞在驱动BM衰竭中起非冗余作用这一假设。临床证据表明CD8 T细胞在BM衰竭中起有害作用，而Foxp3调节性T细胞（Tregs）在维持BM免疫耐受中起有益作用。我们证明，功能性Tregs存在缺陷的白细胞介素-2（IL-2）缺陷小鼠会发生自发性BM衰竭。此外，我们证明CD8 T细胞在BM衰竭的发生发展中起关键作用，这依赖于细胞因子γ干扰素（IFNγ）。CD8 T细胞促进造血干细胞功能障碍和髓系祖细胞耗竭，导致贫血。过继转移实验表明，CD8 T细胞显著加速疾病进展并促进BM中CD4 T细胞的积累。因此，IL-2缺陷小鼠的BM失调是由产生Th1和IFNγ的CD8 T细胞（Tc1）反应介导的。
