CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes
CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes
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DOI：
10.1073/pnas.0906070106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
Mack, Matthias
中科院分区：
文献类型：
--
作者：
Niedermeier, Marianne;Reich, Barbara;Mack, Matthias
纤维细胞是以低频率从造血细胞产生的I型胶原产生细胞。我们已经分析了小鼠中产生纤维细胞所需的白细胞亚群，并表明小鼠纤维细胞是在CD 4（+）T细胞的控制下从CD 11b（+）CD 115（+）Gr 1（+）单核细胞亚群发育而来的。在缺乏CD 4（+）T细胞的情况下，纤维细胞的分化在体外和体内均显著降低。在存在CD 4（+）T细胞的情况下，T细胞活化的特征决定了纤维细胞的发育。CD 4（+）T细胞的多克隆活化诱导可溶性因子的释放，所述可溶性因子完全阻止纤维细胞的生长，并且可以被鉴定为IL-2、TNF、IFN-γ和IL-4。应用IL-2和TNF显著减少单侧输尿管梗阻模型中纤维细胞的出现和纤维化的严重程度。相比之下，在钙调磷酸酶抑制剂（而不是mTOR抑制剂）存在下，CD 4（+）T细胞的活化显著增强了纤维细胞的生长和I型胶原的肾沉积。综上所述，我们发现纤维细胞的分化严重依赖于CD 4（+）T细胞，T细胞活化的背景决定了纤维细胞的发育是被支持还是被阻断。我们的数据可能对预防自身免疫性疾病和移植中的器官纤维化有意义。
Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.