Ekland Eric H, Forster Reinhold, Lipp Martin, Cyster Jason G
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
J Immunol. 2004 Apr 15;172(8):4700-8. doi: 10.4049/jimmunol.172.8.4700.
Results from several mouse tolerance models indicate that autoreactive B cells in peripheral lymphoid organs develop an anergic phenotype, migrate to the boundary between the T cell zone and the B cell follicle (T/B boundary), and undergo rapid cell death. We have used B cells from mice that are double-transgenic for soluble hen egg lysozyme (HEL) and an Ig that recognizes HEL with a high affinity to characterize the mechanisms underlying the migration and elimination of autoreactive B cells. In contrast to the situation for acutely activated B cells, we find that anergic B cells have reduced levels of CXCR5, the receptor for the follicular chemokine, CXCL13, and this contributes to their exclusion from follicles. CCR7 expression is required for follicular exclusion of anergic cells, although up-regulation of the receptor does not appear to be necessary. By TUNEL analysis, we observe that excluded anergic cells die in situ at the T/B boundary. We also show that this elimination occurs via a Fas-independent mechanism. Using CCR7(-/-)Ig(HEL)-transgenic B cells we find that localization to the T/B boundary is not a necessary event to achieve the competitive elimination of autoantigen-binding B cells. These findings characterize the mechanism for follicular exclusion of autoantigen-binding B cells and they indicate that B cells compete for survival by mechanisms that are separate from competition for the follicular niche.
多个小鼠耐受模型的结果表明，外周淋巴器官中的自身反应性B细胞会形成无反应性表型，迁移至T细胞区与B细胞滤泡之间的边界（T/B边界），并迅速发生细胞死亡。我们利用对可溶性鸡卵溶菌酶（HEL）和高亲和力识别HEL的免疫球蛋白进行双转基因的小鼠B细胞，来表征自身反应性B细胞迁移和清除的潜在机制。与急性活化B细胞的情况不同，我们发现无反应性B细胞上滤泡趋化因子CXCL13的受体CXCR5水平降低，这导致它们被排除在滤泡之外。无反应性细胞被滤泡排除需要CCR7表达，不过该受体的上调似乎并非必需。通过TUNEL分析，我们观察到被排除的无反应性细胞在T/B边界原位死亡。我们还表明，这种清除是通过非Fas依赖机制发生的。利用CCR7(-/-)Ig(HEL)转基因B细胞，我们发现定位于T/B边界并非实现自身抗原结合B细胞竞争性清除的必要事件。这些发现表征了自身抗原结合B细胞被滤泡排除的机制，并且表明B细胞通过与滤泡微环境竞争不同的机制来竞争存活。
