Cabatingan Mark S, Schmidt Madelyn R, Sen Ranjan, Woodland Robert T
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
J Immunol. 2002 Dec 15;169(12):6795-805. doi: 10.4049/jimmunol.169.12.6795.
Naive peripheral B cells are maintained in sufficient numbers and diversity to mount effective immune responses against infectious agents. However, the size and repertoire of this B cell pool is constantly diminished by normal cell turnover and Ag activation. Homeostatic (Ag-independent) proliferation in response to B cell depletion is one mechanism to compensate for this cell loss. We have used purified CFSE-labeled B cells and an adoptive transfer model system to show that immature and mature B cells divide in a variety of B cell-deficient (scid, xid, IL-7(-/-), and sublethally irradiated) hosts. Homeostatic B cell proliferation is T cell independent, and B cells that have replicated by this mechanism retain the antigenic phenotype of naive B cells. Replication is significantly reduced in B cell-sufficient normal or B cell-reconstituted immunodeficient recipients by the action of competing mature follicular B cells. Using xid mice and transcription factor knockouts, we show that the activation signal(s) that lead to homeostatic B cell proliferation require Bruton's tyrosine kinase; however, c-Rel, a Bruton's tyrosine kinase-induced NF-kappaB/Rel transcription factor critical for Ag and mitogen stimulation, is dispensable, indicating the uniqueness of this activation pathway. Survival and replication signals can also be separated, because the transcription factor p50 (NF-kappaB1), which is required for the survival of peripheral B cells, is not necessary for homeostatic replication. Homeostatic B cell proliferation provides an Ag-independent mechanism for the maintenance and expansion of naive B cells selected into the mature B cell pool.
初始外周B细胞维持着足够的数量和多样性，以对感染因子发起有效的免疫反应。然而，这个B细胞库的规模和库容量会因正常的细胞更新和抗原激活而不断减少。针对B细胞耗竭的稳态（不依赖抗原）增殖是补偿这种细胞损失的一种机制。我们利用纯化的CFSE标记的B细胞和一个过继转移模型系统，证明未成熟和成熟的B细胞在多种B细胞缺陷（严重联合免疫缺陷、x连锁免疫缺陷、IL-7基因敲除和亚致死剂量照射）宿主中发生分裂。稳态B细胞增殖不依赖T细胞，通过这种机制复制的B细胞保留了初始B细胞的抗原表型。在B细胞充足的正常宿主或B细胞重建的免疫缺陷受体中，由于竞争性成熟滤泡B细胞的作用，复制显著减少。利用x连锁免疫缺陷小鼠和转录因子基因敲除，我们发现导致稳态B细胞增殖的激活信号需要布鲁顿酪氨酸激酶；然而，c-Rel，一种对抗原和丝裂原刺激至关重要的由布鲁顿酪氨酸激酶诱导的NF-κB/Rel转录因子，并非必需，这表明了该激活途径的独特性。存活和复制信号也可以分开，因为外周B细胞存活所需的转录因子p50（NF-κB1）对于稳态复制并非必需。稳态B细胞增殖为维持和扩增被选入成熟B细胞库的初始B细胞提供了一种不依赖抗原的机制。
