LTβR调节淋巴结FRC重建分化的作用机制及其在淋巴结纤维化中的意义

Lymph node (LN) provides particular microenvironments for optimal induction and control of immune responses. These specialized niches are generated and maintained by different sets of vascular and mesenchymal stromal cells. The network of the LN T cell zone is formed by fibroblastic reticular cells (FRCs), which regulate immune homeostasis and reactivity through the production of chemokines, cytokines, and small molecules. It has been suggested that LTβR signaling is critical for the generation, differentiation, and maintenance of FRCs. Previous studies have revealed that failure of FRC differentiation as well as formation of LN T cell zone fibrosis causes severe immune deficiency. In our previous studies, we have showed that the differentiation of FRC in early postnatal period is a multiple step dependent on LTβR signaling. Conditional ablation of LTβR expression in LN FRCs will blockade the maturation of FRCs from immature FRCs which show enhanced expression of myofibroblastic markers. However, critical molecular interactions on FRC differentiation in adult mice during LN remodeling and the molecular details of LN T cell zone fibrosis remain unknown. Here, we will use FRC specific Ccl19-cre transgenic mice, with LTβR signaling related bone marrow chimera mice and specific ablation of the LTβR on Ccl19-cre positive stromal cells, to investigate the mechanisms of LTβR signaling on FRC differentiation in adult mice. Moreover, we will establish a model for LN T cell zone fibrosis via diphtheria toxin-mediated Ccl19-cre positive stromal cell depletion, to determine the roles of LTβR signaling on the development and formation of LN T cell zone fibrosis. This study will provide clues to better understand stromal biology and immune regulation in LN microenvironment, as well as shed a light on further studies of LN fibrosis in HIV patients and provide potential therapeutic options.

淋巴结T细胞区基质细胞(FRC)是调控淋巴结内稳态与功能的重要免疫微环境。FRC损伤是多种病理条件下的常见现象；FRC的重建异常以及严重时伴发的纤维化，均可导致机体免疫功能缺陷。FRC损伤重建的内在机理及其与纤维化的关系目前尚不清楚。我们前期研究发现，LTβR缺陷导致FRC发育阻滞于immFRC，而后者和纤维化组织中异常分化的成肌纤维母细胞有相似表型。我们猜想：LTβR是FRC损伤后重建分化过程中的重要调控分子；该信号通路缺陷将导致FRC异常分化及类成肌纤维母细胞的形成，促进纤维化。本项目将利用特有的Ccl19-cre×iDTR小鼠诱导FRC损伤重建，研究LTβR调控FRC重建分化的细胞和分子机制，揭示FRC异常分化与纤维化的关系；建立淋巴结纤维化模型，验证LTβR通路对纤维化的干预效果。本项目不但有助于深入理解FRC损伤后重建分化的内在规律，而且对淋巴结纤维化的发生机制也提出了新的假说。

淋巴结T细胞区基质细胞(FRC)是调控淋巴结内稳态与功能的重要免疫微环境。FRC损伤是多种病理条件下的常见现象；FRC的重建异常以及严重时伴发的纤维化，均可导致机体免疫功能缺陷。FRC损伤重建的内在机理及其与纤维化的关系目前尚不清楚。我们的研究发现，FRC中LTbetaR的缺陷导致淋巴结中TGFbeta信号通路上调，促进了淋巴组织纤维化的发生。我们发现，LTbetaR信号通路可以抑制TGFbeta信号通路中参与正向调控的因子的表达，从而抑制TGFbeta信号通路诱导的纤维化的发生，保证FRC基质细胞的稳态。进一步我们开拓思路，研究了肠道相关淋巴组织中LTbetaR-RelB信号通路对其中FRC的调控作用和病理意义，我们发现肠道相关淋巴组织中的基质细胞FRC微环境上的RelB信号通路可以通过调控III型天然淋巴细胞(ILC3)上IL-22的表达，达到低于病菌和维护肠道免疫系统稳态平衡的目的。本项目不但对淋巴结纤维化的发生机制提出了新的假说，有助于今后深入研究病理状态下纤维化发生的机制，同时本项目也发现了LTbetaR-RelB信号通路在肠道相关淋巴组织基质细胞上与抗菌相关的新的免疫作用机制与功能，给纤维化和肠道感染等疾病的临床治疗提出新思路。