Niedermeier Marianne, Reich Barbara, Rodriguez Gomez Manuel, Denzel Andrea, Schmidbauer Kathrin, Göbel Nicole, Talke Yvonne, Schweda Frank, Mack Matthias
Department of Internal Medicine II, University Hospital Regensburg, 93042 Regensburg, Germany.
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17892-7. doi: 10.1073/pnas.0906070106. Epub 2009 Oct 6.
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.
纤维细胞是一种产生I型胶原蛋白的细胞，由造血细胞以低频率产生。我们在小鼠中分析了纤维细胞生成所需的白细胞亚群，结果表明，小鼠纤维细胞在CD4(+) T细胞的控制下，从CD11b(+) CD115(+) Gr1(+)单核细胞亚群发育而来。在没有CD4(+) T细胞的情况下，纤维细胞的分化在体外和体内均显著减少。在有CD4(+) T细胞存在时，T细胞激活的特征对纤维细胞的发育起关键决定作用。CD4(+) T细胞的多克隆激活诱导了可溶性因子的释放，这些因子完全阻止了纤维细胞的生长，可鉴定为IL-2、TNF、IFN-γ和IL-4。在单侧输尿管梗阻模型中，应用IL-2和TNF可显著减少纤维细胞的出现和纤维化的严重程度。相反，在钙调神经磷酸酶抑制剂而非mTOR抑制剂存在的情况下激活CD4(+) T细胞，可显著增强纤维细胞的生长和I型胶原蛋白在肾脏的沉积。综上所述，我们表明纤维细胞的分化严重依赖于CD4(+) T细胞，并且T细胞激活的背景决定了纤维细胞的发育是得到支持还是受到阻碍。我们的数据可能对自身免疫性疾病和移植中器官纤维化的预防具有重要意义。
