表观遗传印迹记录的记忆B细胞免疫刺激历史决定记忆B细胞的再分化命运

Past Antigen Exposures are Epigenetically Imprinted and Determine the Memory B Cell Fate Upon Rechallenge

记忆B细胞是长期体液免疫的重要组成部分。在再次被同样的病原体感染之后,记忆B细胞可以迅速转变为产生抗体的浆细胞,或者重新进入生发中心(GCs)进行进一步的抗体体细胞高频突变和亲和力成熟。记忆B细胞重新参与生发中心反应对于产生针对流感病毒和HIV等高度变异病毒的广谱中和抗体至关重要。有报道显示记忆B细胞在抗原再刺激后的分化命运与不同的抗体种型和表面分子相关。然而,转录和表观遗传机制是否影响了这些记忆B细胞的命运尚不清楚。该研究发现,记忆B细胞经历的每次刺激都会以依赖于干扰素调节因子4(IRF4)的方式在表观遗传学上进行记录,这决定了B细胞中两个拮抗转录因子BLIMP1和BACH2的相对水平,进而影响了记忆B细胞在重新刺激时进入生发中心或成为浆细胞的可能性。

Memory B cells are crucial components of long-term humoral immunity.Upon antigen reexposure,memory B cells can rapidly become antibody-producing plasma cells or they can re-enter GCs(germinal centers)to undergo further antibody somatic hypermutation and affinity maturation.Memory B cell re-participation in the GC reaction is thought to be important for generating broadly neutralizing antibodies against highly mutating viruses such as influenza virus and HIV.The fate of memory B cells into plasma cells or GC B cells following antigen re-stimulation is associated with distinct antibody isotypes and memory B cell surface phenotypes.However,whether these memory B cell fates are intrinsically programmed by transcriptional and epigenetic mechanisms was not understood.This study finds that each stimulation experienced by memory B cells is epigenetically recorded in an IRF4-dependent manner,which determines the relative levels of two antagonistic transcription factors BLIMP1 and BACH2 in B cells,and in turn dictates the likelihood that a memory B cell enters a germinal center or becomes a plasma cell upon re-stimulation.