D'Souza Lucas, Gupta Sneh Lata, Bal Vineeta, Rath Satyajit, George Anna
National Institute of Immunology, New Delhi, India.
Immunology. 2017 Dec;152(4):602-612. doi: 10.1111/imm.12800. Epub 2017 Aug 23.
B-cell memory was long characterized as isotype-switched, somatically mutated and germinal centre (GC)-derived. However, it is now clear that the memory pool is a complex mixture that includes unswitched and unmutated cells. Further, expression of CD73, CD80 and CD273 has allowed the categorization of B-cell memory into multiple subsets, with combinatorial expression of the markers increasing with GC progression, isotype-switching and acquisition of somatic mutations. We have extended these findings to determine whether these markers can be used to identify IgM memory phenotypically as arising from T-dependent versus T-independent responses. We report that CD73 expression identifies a subset of antigen-experienced IgM cells that share attributes of functional B-cell memory. This subset is reduced in the spleens of T-cell-deficient and CD40-deficient mice and in mixed marrow chimeras made with mutant and wild-type marrow, the proportion of CD73 IgM memory is restored in the T-cell-deficient donor compartment but not in the CD40-deficient donor compartment, indicating that CD40 ligation is involved in its generation. We also report that CD40 signalling supports optimal expression of CD73 on splenic T cells and age-associated B cells (ABCs), but not on other immune cells such as neutrophils, marginal zone B cells, peritoneal cavity B-1 B cells and regulatory T and B cells. Our data indicate that in addition to promoting GC-associated memory generation during B-cell differentiation, CD40-signalling can influence the composition of the unswitched memory B-cell pool. They also raise the possibility that a fraction of ABCs may represent T-cell-dependent IgM memory.
长期以来，B细胞记忆被认为具有同种型转换、体细胞突变且源自生发中心（GC）的特征。然而，现在很清楚的是，记忆库是一个复杂的混合物，其中包括未转换和未突变的细胞。此外，CD73、CD80和CD273的表达使得B细胞记忆能够被分类为多个亚群，随着GC进展、同种型转换和体细胞突变的获得，这些标志物的组合表达增加。我们扩展了这些发现，以确定这些标志物是否可用于从表型上鉴定IgM记忆是源自T细胞依赖性反应还是T细胞非依赖性反应。我们报告称，CD73表达可识别出一部分经历过抗原刺激的IgM细胞，这些细胞具有功能性B细胞记忆的特征。在T细胞缺陷和CD40缺陷小鼠的脾脏中，以及在用突变型和野生型骨髓构建的混合骨髓嵌合体中，该亚群数量减少，在T细胞缺陷的供体区室中，CD73 IgM记忆的比例得以恢复，但在CD40缺陷的供体区室中则未恢复，这表明CD40连接参与了其产生过程。我们还报告称，CD40信号传导支持脾脏T细胞和年龄相关B细胞（ABC）上CD73的最佳表达，但不支持其他免疫细胞如中性粒细胞、边缘区B细胞、腹腔B-1 B细胞以及调节性T细胞和B细胞上CD73的最佳表达。我们的数据表明，除了在B细胞分化过程中促进与GC相关的记忆产生外，CD40信号传导还可影响未转换记忆B细胞库的组成。这些数据还增加了一种可能性，即一部分ABC可能代表T细胞依赖性IgM记忆。
