Lymphoid Structure in Tolerance

描述（由申请人提供）：我们的初步数据表明，在耐受期间，在高内皮小静脉（HEV）腔面附近淋巴结（LN）的T细胞区存在同种异体抗原特异性的T细胞和浆细胞样DC （pDC）聚集。在这些细胞簇中，T细胞启动或发育为CD4+CD25+调节性T细胞（Treg）， B细胞在这些细胞簇中呈现特异性同种异体抗原，LN基质细胞结构在排斥反应和耐受反应中发生形态学改变。我们假设LN中的这些多细胞集群相互作用是诱导和维持耐受性的关键。具体来说，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，并最终决定了是否诱导排斥或耐受。这一新的假说整合了许多受体-配体和细胞-细胞相互作用，并将它们置于次级淋巴器官结构的背景下。我们目前资助的研究主要集中在Treg的命运和分化，T细胞的迁移和运输，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，但我们新的初步数据表明，B细胞、基质细胞、基质纤维和其他LN元件在导致耐受的群集相互作用中，在LN中起着新的重要作用。为了研究这些新的细胞和结构元件在LN簇相互作用中的作用，我们提出以下具体目标：利用移植模型确定B细胞在LN结构中的耐受性作用，该模型允许特异性跟踪抗原特异性T细胞和特异性异体抗原呈递抗原呈递细胞（ARC），我们将研究B细胞在T- apc聚集相互作用导致耐受性过程中在LN中的作用。分析将集中在B细胞ARC功能，趋化因子的产生和免疫球蛋白的产生。具体目标2。我们将研究LN中基质细胞和基质细胞衍生元件在耐受过程中T-APC聚集相互作用中的作用。具体目标3。确定不变先天细胞免疫应答在耐受性中的作用我们将确定对先天和不变信号作出反应的其他细胞元件如何影响T-APC簇相互作用、LN结构和耐受性。

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.