Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice.
Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice.
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T细胞和B细胞静止的损失是在GIMAP5缺陷型小鼠中微生物菌群依赖的浪费疾病和肠炎的发作之前。
DOI：
10.4049/jimmunol.0903164
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Hoebe K
中科院分区：
文献类型：
--
作者：
Barnes MJ;Aksoylar H;Krebs P;Bourdeau T;Arnold CN;Xia Y;Khovananth K;Engel I;Sovath S;Lampe K;Laws E;Saunders A;Butcher GW;Kronenberg M;Steinbrecher K;Hildeman D;Grimes HL;Beutler B;Hoebe K
免疫系统的稳态控制涉及确保造血衍生细胞的自身耐受性、存活和静止的机制。在这项研究中，我们证明了免疫相关蛋白（Gimap）5的GTdR调节淋巴细胞和造血祖细胞中的这些过程。作为Gimap 5的P环中的隐性N-乙基-N-亚硝基脲诱导的种系突变的结果，在纯合突变小鼠中发生淋巴细胞减少症、肝髓外造血、体重减轻和肠道炎症。用Gimap 5缺陷细胞重建的辐射胎肝嵌合小鼠体重减轻并变得淋巴细胞减少，证明了Gimap 5的造血细胞内在功能。尽管Gimap 5缺陷型CD 4 + T细胞和B细胞似乎经历正常发育，但它们在Ag受体刺激下不能增殖，尽管NF-κB、MAP激酶和Akt活化正常发生。此外，在Gimap 5缺陷小鼠中，CD 4 + T细胞采用CD 44高、CD 62低、CD 69低表型，并显示IL-7 r α表达降低，T依赖性和T非依赖性B细胞应答被消除。因此，Gimap 5缺陷影响Ag受体诱导的增殖和淋巴细胞静止所需的非经典信号通路。抗生素治疗或Rag充足的脾细胞的过继转移改善了肠道炎症和体重减轻，表明微生物植物群引发的免疫应答导致Gimap 5缺陷小鼠的发病率。这些数据确立了Gimap 5作为造血完整性和淋巴细胞稳态的关键调节因子。
Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea–induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4+ T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-κB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4+ T cells adopt a CD44high CD62Llow CD69low phenotype and show reduced IL-7rα expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor–induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.
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