Lymphoid Structure in Tolerance

描述(申请人提供)：我们的初步数据显示，在耐受期间，在高内皮微静脉(HEV)开口面附近的淋巴结(LN)的T细胞区，存在同种抗原特异性的T细胞和浆细胞样树突状细胞(PDC)聚集。在这些细胞簇中，T细胞经历启动或发育为新的CD4+CD25+调节性T细胞(Treg)，B细胞在这些细胞簇中呈递特定的同种异体抗原，LN基质细胞的结构在排斥和耐受中发生形态变化。我们假设LN中的这些多细胞聚集性相互作用是诱导和维持耐受的关键。具体地说，T-APC(PDC、B细胞)与LNS中其他细胞和结构的相互作用决定了T细胞的迁移、定位、增殖和成熟，最终决定了T细胞是否诱导排斥或耐受。这一新的假设整合了许多受体-配体和细胞-细胞相互作用，并将这些放在次级淋巴器官结构的背景下。我们目前资助的研究集中在Treg的命运和分化，T细胞的迁移和贩运，以及T-PDC相互作用的作用。虽然T细胞反应在移植耐受中起着核心作用，但我们的新的初步数据表明，B细胞、基质细胞、基质纤维和其他LN元素在导致耐受的群集性相互作用中，在LN中扮演着新的和重要的角色。为了研究这些新的细胞和结构元件在LN簇状相互作用中的作用，我们提出了以下特定的目的：1.确定LN结构中B细胞在耐受中的作用使用移植模型，该模型允许对抗原特异性T细胞和同种异体抗原提呈细胞(ARC)进行特异性追踪，我们将研究B细胞在T-APC簇状相互作用中导致LN耐受的作用。分析将集中在B细胞ARC功能、趋化因子产生和免疫球蛋白产生上。具体目的2.确定耐受所必需的LN间质结构和细胞我们将研究LN中的基质细胞和基质细胞衍生元件在T-APC在耐受过程中的聚集相互作用中的作用。具体目标3.确定不变的先天细胞免疫反应在耐受中的作用我们将确定其他对先天和不变信号做出反应的细胞元件如何影响T-APC聚集相互作用、LN结构和耐受。

DESCRIPTION (provided by applicant): Our preliminary data demonstrate that during tolerization there is alloantigen specific clustering of T cells and plasmacytoid DC (pDC) in the T cell areas of the lymph node (LN) near the abluminal surface of the high endothelial venules (HEV). Within these clusters T cells undergo priming or development into de novo CD4+CD25+ regulatory T cells (Treg), B cells present specific alloantigen in these cell clusters, and LN stromal cells structures are morphologically altered in rejection versus tolerization. We hypothesize these multicellular clustered interactions in the LN are key to the induction and maintenance of tolerance. Specifically, the interaction of T-APC (pDC, B cells) along with other cells and structures in LNs determines T cell migration, positioning, proliferation, and maturation, and ultimately whether rejection or tolerance are induced. This novel hypothesis integrates many receptor-ligand and cell-cell interactions, and places these in the context of secondary lymphoid organ structure. Our currently funded investigations are focused on the fate and differentiation of Treg, T cell migration and trafficking, and the role of T-pDC interactions. While T cell responses have a central role in transplantation tolerance, our new preliminary data suggest novel and important roles in the LN for B cells, stromal cells, stromal fibers, and other LN elements in the clustered interaction that leads to tolerization. To investigate the role of these novel cellular and structural elements in LN clustered interactions, we propose the following specific aims: Specific Aim 1. Determine the roles of B cells in LN structure in tolerance using a transplant model that allows the specific tracking of antigen specific T cells and specific alloantigen presenting antigen presenting cells (ARC), we will investigate the roles of B cells in the LN during the T-APC clustered interaction that results in tolerization. Analyses will focus on B cell ARC function, chemokine production, and immunoglobulin production. Specific Aim 2. Determine the LN stromal structures and cells essential for tolerance We will investigate the role of stromal cells and stromal cell derived elements in the LN in the T-APC clustered interaction during tolerization. Specific Aim 3. Determine the role of invariant innate cellular immune responses in tolerance We will determine how other cellular elements, that respond to innate and invariant signals, affect the T-APC clustered interaction, LN structure, and tolerization.