Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis [ZE303]

Immunoglobulin A (IgA) is the predominant immunoglobulin isotype in mammals, primarily secreted at type I mucosal surfaces. Despite its abundance, the precise role of secretory IgA in the intestinal lumen, where it coats a diverse array of commensal microbiota, has remained elusive. Our study reveals that germinal center IgA responses are essential for preventing chronic colonization of the gut by specific viruses. In absence of IgA, chronic viral colonization triggers an antigen-driven expansion of CD8αβ+ intraepithelial lymphocytes (IELs). Although, these IELs are unable to clear the virus, they contribute to maintaining homeostasis by regulating its load and type-I interferon responses. Consequently, IgA deficiency increases susceptibility to colitis in genetically susceptible host or following chemical induction, but only in presence of viral pathobionts requiring IgA for their clearance. These findings underscore the potential vulnerability of IgA deficient individuals to immunopathology when exposed to selective viral pathobionts. RNA-seq profiling of the intestinal tissue (jejunum, ileum) or sorted epithelial cells (jejunum) from Ighasec+/- and Ighasec-/- mice treated with isotype or anty-CD8b depleting antibody for 3 weeks.

免疫球蛋白A（Immunoglobulin A, IgA）是哺乳动物体内的主要免疫球蛋白亚型，主要在I型黏膜表面分泌。尽管其丰度颇高，但分泌型免疫球蛋白A（secretory IgA, sIgA）在肠腔中的确切功能始终不明——肠腔中sIgA可包裹种类繁多的共生微生物群。本研究揭示，生发中心免疫球蛋白A（germinal center IgA）应答对于阻断特定病毒在肠道内的慢性定植至关重要。当缺乏IgA时，慢性病毒定植会触发抗原驱动的CD8αβ+上皮内淋巴细胞（intraepithelial lymphocytes, IELs）增殖。尽管此类上皮内淋巴细胞无法清除病毒，但它们可通过调控病毒载量与I型干扰素应答，协助维持肠道稳态。因此，在遗传易感宿主中，或经化学诱导后，免疫球蛋白A缺乏会提升结肠炎易感性，但该效应仅在存在需要IgA介导清除的病毒致病性共生菌（viral pathobionts）时才会显现。上述研究结果凸显出，免疫球蛋白A缺乏个体在接触特定病毒致病性共生菌时，存在发生免疫病理损伤的潜在风险。本数据集包含对经如下处理的小鼠样本的RNA测序（RNA-seq）分析：对Ighasec+/-与Ighasec-/-小鼠给予同型对照抗体或抗CD8b耗竭抗体，持续给药3周后，采集其肠道组织（空肠、回肠）或分选得到的空肠上皮细胞进行测序。