Pasztoi Maria, Pezoldt Joern, Beckstette Michael, Lipps Christoph, Wirth Dagmar, Rohde Manfred, Paloczi Krisztina, Buzas Edit Iren, Huehn Jochen
Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Eur J Immunol. 2017 Dec;47(12):2142-2152. doi: 10.1002/eji.201746960. Epub 2017 Sep 15.
Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN-iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-β when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-β-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders.
肠道调节性T细胞（Tregs）在外周对共生菌和食源抗原的耐受性中起着关键作用。因此，与引流皮肤的外周淋巴结（pLNs）相比，引流肠道的肠系膜淋巴结（mLNs）是外周从头诱导Tregs的有效部位，并且我们最近表明淋巴结基质细胞对这一过程有重要贡献。在此，我们旨在揭示潜在的分子机制，并从mLNs和pLNs中生成永生化的成纤维网状细胞系（iFRCs），从而能够对这种罕见的基质细胞亚群进行无限制的研究。与我们之前的发现一致，与pLN-iFRCs相比，mLN-iFRCs表现出更高的Treg诱导能力。聚焦于分泌分子的RNA测序分析显示，与pLN-iFRCs相比，mLN-iFRCs具有更具耐受性的表型。值得注意的是，与pLN-iFRCs来源的微泡相比，mLN-iFRCs产生了大量携带更高水平TGF-β的微泡（MVs），并且这些细胞间通讯的新参与者被证明是mLN-iFRCs耐受性特性的原因。因此，源自mLNs的基质细胞通过利用携带TGF-β的MVs促进从头诱导Tregs，从而对外周耐受性做出贡献。这一发现为从头诱导Tregs的亚细胞/分子机制提供了新的见解，并可能成为未来治疗炎症性疾病的有前景的治疗工具。
