Abstract：
Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in nonlymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages, or CCL19 but crucially depends on type I interferon (IFN-I). Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTβR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTβR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs.
摘要：
三级淋巴结构（TLS）类似于二级淋巴器官的滤泡，在炎症和癌症期间在非淋巴组织中发育。哪些细胞类型和信号驱动TLS的发展在很大程度上是未知的。为了调查肺部TLS发展的早期事件，我们反复滴注p（I：C）加卵白蛋白（Ova）鼻内。这种诱导的TLS范围从淋巴细胞聚集体到含有生发中心的有组织和功能结构。我们发现TLS发育独立于FAP+成纤维细胞，肺泡巨噬细胞，或CCL19，但关键取决于I型干扰素（IFN-I）。机械上,IFN-I启动两个协同途径，最终导致TLS的发展。一方面,IFN-I诱导淋巴细胞中的淋巴毒素（LT）α，通过LTβR信号传导刺激基质细胞产生吸引B细胞的趋化因子CXCL13。另一方面,IFN-I被产生T细胞吸引趋化因子CXCL9、CXCL10以及独立于LTβR的CCL19和CCL21的基质细胞感知。因此,B细胞聚集体在一周内形成,而滤泡树突状细胞和生发中心在3周后出现。因此，IFN-I和抗原的持续产生对于在肺中诱导功能性TLS是必需的。
