1 Meakins Christie Laboratories, and.
Am J Respir Cell Mol Biol. 2013 Oct;49(4):563-70. doi: 10.1165/rcmb.2012-0356OC.
Allergic asthma is a heterogeneous disease with no curative therapies. T cells infiltrate the airway smooth muscle (ASM) layer and may be implicated in airway remodeling and the increase of ASM mass, a cardinal feature of asthma. The mechanism by which CD4(+) T cells drive airway remodeling remains unknown. This study sought to determine the T cell-mediated mechanism of ASM cell proliferation. We hypothesized that CD4(+) T cells adhere to ASM cells via CD44, and induce ASM cell proliferation through the activation of the epidermal growth factor receptor (EGFR). A coculture model showed that the contact of antigen-stimulated CD4(+) T cells with ASM cells induced high levels of EGFR ligand expression in CD4(+) T cells and the activation of matrix metalloproteinase (MMP)-9, required for the shedding of EGFR ligands. The inhibition of EGFR and MMP-9 prevented the increase of ASM cell proliferation after coculture. The hyaluronan receptor CD44 is the dominant mediator of the tight adherence of T cells to ASM and is colocalized with MMP-9 on the cell surface. Moreover, the neutralization of CD44 prevents ASM cell hyperplasia. These data provide a novel mechanism by which antigen-stimulated CD4(+) T cells induce the remodeling indicative of a direct trophic role for CD4(+) T cells.
变应性哮喘是一种异质性疾病，目前尚无治愈疗法。T 细胞浸润气道平滑肌（ASM）层，可能与气道重塑和 ASM 质量增加有关，这是哮喘的一个主要特征。CD4(+) T 细胞驱动气道重塑的机制尚不清楚。本研究旨在确定 CD4(+) T 细胞介导的 ASM 细胞增殖的机制。我们假设 CD4(+) T 细胞通过 CD44 与 ASM 细胞黏附，并通过表皮生长因子受体（EGFR）的激活诱导 ASM 细胞增殖。共培养模型显示，抗原刺激的 CD4(+) T 细胞与 ASM 细胞接触诱导 CD4(+) T 细胞中高水平的 EGFR 配体表达，并激活基质金属蛋白酶（MMP）-9，这是 EGFR 配体脱落所必需的。EGFR 和 MMP-9 的抑制可防止共培养后 ASM 细胞增殖增加。透明质酸受体 CD44 是 T 细胞与 ASM 紧密黏附的主要介质，与 MMP-9 一起位于细胞表面。此外，CD44 的中和可防止 ASM 细胞增生。这些数据提供了一种新的机制，即抗原刺激的 CD4(+) T 细胞诱导提示 CD4(+) T 细胞具有直接营养作用的重塑。
