Alexander Katie L, Katz Jannet, Elson Charles O
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL, United States of America.
PLoS One. 2017 Jul 27;12(7):e0181866. doi: 10.1371/journal.pone.0181866. eCollection 2017.
Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD). One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg)- Immunoglobulin A (IgA) pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB) via the A2 linker of CT. Both dendritic cells (DCs) and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA) signaling but was inhibited by neutralization of TGF-β. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR) signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.
在宿主细胞与微生物群之间营造一种共生环境至关重要，这种关系的失调与多种免疫紊乱相关，包括代谢性疾病、皮肤病、哮喘、过敏和炎症性肠病（IBD）。维持体内平衡的一个重要机制是针对微生物群抗原的保护性调节性T细胞（Treg）-免疫球蛋白A（IgA）途径，其中Tregs维持体内平衡并为IgA+B细胞提供关键的生存因子。为了增强Treg-IgA途径，我们构建了一种融合蛋白CBirTox，它由微生物鞭毛蛋白CBir1羧基末端的一部分组成，通过霍乱毒素（CT）的A2接头与霍乱毒素B亚基（CTB）基因偶联。用CBirTox脉冲处理的树突状细胞（DCs）和B细胞在体外均能选择性诱导功能性CD4+Foxp3+Tregs，并且CBirTox在体内增加了CD4+Foxp3+细胞数量。诱导的Foxp3表达独立于视黄酸（RA）信号，但被TGF-β的中和所抑制。CBirTox处理B细胞可下调雷帕霉素哺乳动物靶标（mTOR）信号。此外，用CBirTox脉冲处理的DCs可诱导幼稚B细胞大量产生IgA。这些数据共同表明，CBirTox代表了一种在宿主-微生物群界面增强Treg-IgA途径的新方法。
