Follicular dendritic cells and B cell tolerance

描述（由申请人提供）：滤泡树突状细胞（fdc）被认为是次要淋巴组织的关键基质成分，它保留抗原和免疫复合物，但也对环境刺激作出反应，并提供可溶性因子，包括BAFF，影响晚期B细胞分化。我们假设fdc可能对自身抗原的保留也很重要，这样可以捕获短暂或偶发存在的自身抗原。我们认为，fdc保留自身抗原可能在持续消除自身反应性B细胞中发挥重要作用，因为它们在脾脏中作为“过渡性”B细胞完成了晚期成熟。这一发育阶段的选择事件尚未被很好地理解，并与骨髓中早期B细胞成熟的描述形成对比。在这个提议中，我们介绍了一种新的基于膜结合自身抗原在fdc上条件表达的B细胞耐受小鼠模型。我们提供了fdc在外周B细胞耐受中发挥作用的第一个直接证据。在拟议的工作中，我们将：(i)表征fdc结合的自身抗原施加的晚期B细胞发育阻滞。（ii）利用强迫表达在过渡性和成熟B细胞中差异表达的microrna来鉴定T1细胞耐受敏感性的重要基因。

DESCRIPTION (provided by applicant): Follicular dendritic cells (FDCs) are recognized as critical stromal components of the secondary lymphoid tissues that retain antigen and immune complexes, but also respond to environmental stimuli and provide soluble factors, including BAFF, that impact late B cell differentiation. We hypothesize that FDCs may also be important for the retention of self-antigens such that the transient or episodic presence of a self-antigen can be captured. We propose that retention of autoantigens by FDCs may provide an important function in the continual elimination of autoreactive B cells as they complete late maturation in the spleen as "transitional" B cells. Selection events at this stage of development are not well understood and contrast with those described for early B cell maturation in the bone marrow. In this proposal, we introduce a new mouse model of B cell tolerance based upon the conditional expression of a membrane-bound self-antigen on FDCs. We provide the first direct evidence for FDCs as having a role in peripheral B cell tolerance. In the proposed work, we will: (i) Characterize the late B cell development block imposed by FDC-bound self-antigen. (ii) Use forced expression of microRNAs that are differential expressed in transitional and mature B cells to identify genes that are important for tolerance susceptibility of T1 cells.