Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, WI, USA.
Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, WI, USA.
Cell Rep. 2020 Jan 28;30(4):1039-1051.e5. doi: 10.1016/j.celrep.2019.12.081.
Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12α chain (p35) subunits, yet the forms that IL-35 assume and its role in peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in Treg C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3 gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogen-specific Foxp3 and Foxp3 (iTr35) T cells. Furthermore, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance.
白细胞介素-35 (IL-35) 是一种免疫抑制细胞因子，由 Epstein-Barr 病毒诱导蛋白 3 (Ebi3) 和 IL-12α 链 (p35) 亚基组成，但 IL-35 的存在形式及其在外周耐受中的作用仍不清楚。我们在 Treg C57BL/6 报告小鼠中诱导 CBA 特异性、IL-35 产生的调节性 T (Treg) 细胞，并通过表达 Ebi3 基因报告基因加 Ebi3 和 p35 蛋白来鉴定 IL-35 产生细胞。奇怪的是，IL-35 的两个亚基都显示在同种抗原特异性 Foxp3 和 Foxp3 (iTr35) T 细胞的表面。此外，尽管 IL-35 产生细胞很少，但它们会在针对 25 到 100 倍数量的 T 和 B 淋巴细胞的细胞外囊泡 (EVs) 上分泌 Ebi3 和 p35，导致它们获得表面 IL-35。当 EV 产生被抑制或 Treg 细胞中 Ebi3 被基因删除时，这种表面 IL-35 就不存在了。EV 独特的将 IL-35 包裹在旁观者淋巴细胞上的能力，促进非 Treg 细胞的耗竭和次级抑制，确定了一种新的感染性耐受机制。
