Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.
Department of Allergy and Clinical Immunology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France.
Sci Immunol. 2019 Sep 6;4(39). doi: 10.1126/sciimmunol.aaw2910.
At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (T) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of T in murine skin and lungs revealed that T in skin are transcriptionally distinct and skewed toward T helper 2 (T2) differentiation. When compared with T in lung, skin T preferentially expressed high levels of GATA3, the master T2 transcription factor. Genes regulated by GATA3 were highly enriched in skin "T2 T" subsets. In functional experiments, T depletion resulted in a preferential increase in T2 cytokine production in skin. Both acute depletion and chronic reduction of T resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of in T resulted in an exacerbation of T2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that T play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3.
在纤维化疾病的中心，是组织成纤维细胞的异常激活。免疫系统增强成纤维细胞激活的细胞和分子机制已经被描述；然而，对于免疫系统如何控制组织中成纤维细胞的功能，知之甚少。在这里，我们确定调节性 T 细胞（T）是皮肤中成纤维细胞激活的重要调节者。对小鼠皮肤和肺部 T 的批量细胞和单细胞分析表明，皮肤中的 T 在转录上是不同的，并偏向于辅助性 T2（T2）分化。与肺部的 T 相比，皮肤 T 优先表达高水平的 GATA3，这是 T2 转录因子的主要转录因子。受 GATA3 调节的基因在皮肤“T2 T”亚群中高度富集。在功能实验中，T 耗竭导致皮肤中 T2 细胞因子产生的优先增加。急性耗竭和慢性减少 T 都导致自发性皮肤成纤维细胞激活、促纤维化基因表达和真皮纤维化，所有这些在博来霉素诱导的皮肤硬化小鼠模型中都被加剧。T 中的特异性缺失导致 T2 细胞因子分泌的加剧，这种情况在皮肤中更为明显，导致成纤维细胞激活和真皮纤维化增强。总之，我们证明 T 在调节皮肤中成纤维细胞激活方面起着关键作用，其通过表达一种独特的组织限制性转录程序来实现，至少部分是由 GATA3 介导的。
