CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
J Immunol. 2020 Aug 1;205(3):853-863. doi: 10.4049/jimmunol.2000197. Epub 2020 Jun 26.
As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell-IEC cross-talk, remain largely unknown. In this study, using conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during infection for host defense but not homeostatic maintenance in the naive state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT), but not LIGHT, and type 3 innate lymphoid cells (ILC3s), but not conventional T cells, are required for MUC2-dependent control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in the defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and and required for the anti- response. Therefore, our data together suggest a previously unrecognized ILC3-IEC interaction and LT-LTβR-RelB signaling axis governing GC differentiation and function during infection for host defense.
作为肠上皮细胞（IECs）的一个专门亚群，杯状细胞（GCs）在通过粘蛋白产生来响应抗菌作用方面发挥着重要作用。然而，在感染过程中涉及 GC 分化和功能的调节机制，特别是免疫细胞与 IEC 之间的串扰作用，在很大程度上仍然未知。在这项研究中，我们使用条件性敲除小鼠证明了 LTβR 在 IEC 上的表达，对于 GC 增生和感染期间的粘蛋白 2（MUC2）表达是必需的，这对于宿主防御很重要，但在未感染状态下对于维持内稳态则不是必需的。对单基因缺陷型小鼠的分析表明，配体淋巴毒素（LT）而不是 LIGHT，以及 3 型固有淋巴细胞（ILC3），而不是常规 T 细胞，对于依赖 MUC2 的控制是必需的。在 ILC3 中条件性缺失 LT 进一步证实了 ILC3 来源的 LT 信号的重要性。缺乏 ILC3 来源的 LT 或 IEC 来源的 LTβR 导致与 GC 分化相关的基因表达缺陷，但与 IEC 增殖和细胞死亡无关，通过 Ki-67 和 Annexin V 染色发现这两者均正常。此外，还发现 IEC 中的替代 NF-κB 信号通路（涉及 RelB）对于 GC 分化相关基因的表达和 防御是必需的。因此，我们的数据共同表明，在感染过程中，一个以前未被认识到的 ILC3-IEC 相互作用和 LT-LTβR-RelB 信号轴调节 GC 分化和功能，以实现宿主防御。
