Wu Yongzhong, Sukumar Selvakumar, El Shikh Mohey Eldin, Best Al M, Szakal Andras K, Tew John G
Department of Microbiology, Immunology Group, Virginia Commonwealth University, Richmond 23298-0678, USA.
J Immunol. 2008 Jan 1;180(1):281-90. doi: 10.4049/jimmunol.180.1.281.
We reasoned that immune complex (IC)-bearing follicular dendritic cells (FDCs) promote somatic hypermutation (SHM). This hypothesis was tested in murine germinal center reactions induced in vitro by coculturing 6-day (4-hydroxy-3-nitrophenyl) acetyl-primed but unmutated lambda+ B cells, chicken gamma-globulin (CGG) memory T cells, FDCs, and ICs (anti-CGG plus NP-CGG). Mutations in primed lambda+ B cells were obtained only when both FDCs and immunogen were present. FDCs alone promoted B cell survival and Ab production but there were no mutations without more immunogen. Moreover, the mutation rate was enhanced when FDCs were activated. Trapped ICs ranged from 200 to 500 A apart on FDC membranes and this correlated with the periodicity known to optimally signal BCRs. FDCs are unique in their ability to retain ICs for months and a second signal mediated by FDC-ICs appeared to be needed a week or more after immunization by immunogen persisting on FDCs. However, the time needed to detect extensive SHM could be reduced to 7 days if ICs were injected together with memory T cells in vivo. In marked contrast, no mutations were apparent after 7 days in vivo if ICs were replaced by free Ag that would not load on FDCs until Ab was produced. The data suggest that specific Ab production leads to the following events: Ab encounters Ag and ICs are formed, ICs are trapped by FDCs, B cells are stimulated by periodically arranged Ag in ICs on FDCs, and this late antigenic signal promotes SHM.
我们推断，携带免疫复合物（IC）的滤泡树突状细胞（FDC）可促进体细胞超突变（SHM）。该假设在体外诱导的小鼠生发中心反应中得到验证，方法是将6天龄的（4-羟基-3-硝基苯基）乙酰化预致敏但未发生突变的λ⁺ B细胞、鸡γ球蛋白（CGG）记忆T细胞、FDC和IC（抗CGG加NP-CGG）共同培养。只有当FDC和免疫原均存在时，预致敏的λ⁺ B细胞才会发生突变。单独的FDC可促进B细胞存活和抗体产生，但没有更多免疫原时则不会发生突变。此外，当FDC被激活时，突变率会提高。FDC膜上捕获的IC彼此相距200至500埃，这与已知能最佳激活BCR的周期性相关。FDC在保留IC数月的能力方面独具特色，由FDC-IC介导的第二个信号似乎在免疫原在FDC上持续存在免疫一周或更长时间后才需要。然而，如果在体内将IC与记忆T细胞一起注射，则检测到广泛SHM所需的时间可缩短至7天。与之形成鲜明对比的是，如果将IC替换为游离抗原，在体内7天后则无明显突变，游离抗原在产生抗体之前不会负载到FDC上。数据表明，特异性抗体产生会引发以下事件：抗体遇到抗原并形成IC，IC被FDC捕获，B细胞被FDC上IC中周期性排列的抗原刺激，而这种晚期抗原信号促进SHM。
