Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany.
J Exp Med. 2012 Feb 13;209(2):365-77. doi: 10.1084/jem.20111980. Epub 2012 Jan 16.
Intestinal immunoglobulin A (IgA) ensures host defense and symbiosis with our commensal microbiota. Yet previous studies hint at a surprisingly low diversity of intestinal IgA, and it is unknown to what extent the diverse Ig arsenal generated by somatic recombination and diversification is actually used. In this study, we analyze more than one million mouse IgA sequences to describe the shaping of the intestinal IgA repertoire, its determinants, and stability over time. We show that expanded and infrequent clones combine to form highly diverse polyclonal IgA repertoires with very little overlap between individual mice. Selective homing allows expanded clones to evenly seed the small but not large intestine. Repertoire diversity increases during aging in a dual process. On the one hand, microbiota-, T cell-, and transcription factor RORγt-dependent but Peyer's patch-independent somatic mutations drive the diversification of expanded clones, and on the other hand, new clones are introduced into the repertoire of aged mice. An individual's IgA repertoire is stable and recalled after plasma cell depletion, which is indicative of functional memory. These data provide a conceptual framework to understand the dynamic changes in the IgA repertoires to match environmental and intrinsic stimuli.
肠道免疫球蛋白 A（IgA）确保了宿主防御和与共生微生物群落的共生。然而，先前的研究表明肠道 IgA 的多样性出人意料地低，并且不知道体细胞重组和多样化产生的多样化 Ig 武器库在多大程度上实际被利用。在这项研究中，我们分析了超过一百万种小鼠 IgA 序列，以描述肠道 IgA 库的形成、其决定因素以及随时间的稳定性。我们表明，扩展和罕见的克隆组合形成高度多样化的多克隆 IgA 库，个体小鼠之间几乎没有重叠。选择性归巢允许扩展的克隆均匀地播种小肠，但不是大肠。在衰老过程中，多样性会以双重过程增加。一方面，依赖于微生物群、T 细胞和转录因子 RORγt 但不依赖于派尔集合淋巴结的体细胞突变驱动扩展克隆的多样化，另一方面，新的克隆被引入老年小鼠的库中。个体的 IgA 库是稳定的，并在浆细胞耗竭后被召回，这表明存在功能记忆。这些数据为理解 IgA 库的动态变化以匹配环境和内在刺激提供了一个概念框架。
