Kasheta Melissa, Painter Corrie A, Moore Finola E, Lobbardi Riadh, Bryll Alysia, Freiman Eli, Stachura David, Rogers Arlin B, Houvras Yariv, Langenau David M, Ceol Craig J
Program in Molecular Medicine and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA.
J Exp Med. 2017 Dec 4;214(12):3519-3530. doi: 10.1084/jem.20162084. Epub 2017 Oct 24.
Regulatory T (T reg) cells are a specialized sublineage of T lymphocytes that suppress autoreactive T cells. Functional studies of T reg cells in vitro have defined multiple suppression mechanisms, and studies of T reg-deficient humans and mice have made clear the important role that these cells play in preventing autoimmunity. However, many questions remain about how T reg cells act in vivo. Specifically, it is not clear which suppression mechanisms are most important, where T reg cells act, and how they get there. To begin to address these issues, we sought to identify T reg cells in zebrafish, a model system that provides unparalleled advantages in live-cell imaging and high-throughput genetic analyses. Using a orthologue as a marker, we identified CD4-enriched, mature T lymphocytes with properties of T reg cells. Zebrafish mutant for displayed excess T lymphocytes, splenomegaly, and a profound inflammatory phenotype that was suppressed by genetic ablation of lymphocytes. This study identifies T reg-like cells in zebrafish, providing both a model to study the normal functions of these cells in vivo and mutants to explore the consequences of their loss.
调节性T（Treg）细胞是T淋巴细胞的一个特殊亚系，可抑制自身反应性T细胞。体外对Treg细胞的功能研究已确定了多种抑制机制，对Treg细胞缺陷的人类和小鼠的研究也明确了这些细胞在预防自身免疫中所起的重要作用。然而，关于Treg细胞在体内如何发挥作用仍存在许多问题。具体而言，尚不清楚哪些抑制机制最为重要、Treg细胞在何处发挥作用以及它们如何到达那里。为了开始解决这些问题，我们试图在斑马鱼中鉴定Treg细胞，斑马鱼是一种在活细胞成像和高通量遗传分析方面具有无与伦比优势的模型系统。我们使用一种直系同源物作为标记，鉴定出了具有Treg细胞特性的富含CD4的成熟T淋巴细胞。缺乏该直系同源物的斑马鱼突变体表现出T淋巴细胞过多、脾肿大以及一种严重的炎症表型，而淋巴细胞的基因消融可抑制这种表型。这项研究在斑马鱼中鉴定出了Treg样细胞，既提供了一个在体内研究这些细胞正常功能的模型，也提供了探索其缺失后果的突变体。
