Madan Rajat, Demircik Filiz, Surianarayanan Sangeetha, Allen Jessica L, Divanovic Senad, Trompette Aurelien, Yogev Nir, Gu Yuanyuan, Khodoun Marat, Hildeman David, Boespflug Nicholas, Fogolin Mariela B, Gröbe Lothar, Greweling Marina, Finkelman Fred D, Cardin Rhonda, Mohrs Markus, Müller Werner, Waisman Ari, Roers Axel, Karp Christopher L
Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
J Immunol. 2009 Aug 15;183(4):2312-20. doi: 10.4049/jimmunol.0900185. Epub 2009 Jul 20.
IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8(+) T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.
白细胞介素-10在抑制炎症反应的活力中起核心作用，但在许多疾病模型中，这种反向调节细胞因子的关键细胞来源仍具有推测性。利用一种新型的白细胞介素-10转录报告基因小鼠，我们发现在基线状态以及多种体内免疫攻击模型中，外周淋巴组织中表达白细胞介素-10的细胞中，B细胞（包括浆细胞）出人意料地占主导地位。使用一种新型的B细胞特异性白细胞介素-10基因敲除小鼠发现，在小鼠巨细胞病毒感染期间，B细胞来源的白细胞介素-10非冗余地降低病毒特异性CD8(+) T细胞反应和浆细胞扩增，并且在用抗IgD的外源抗体攻击后适度抑制免疫激活。相比之下，在内毒素血症期间，B细胞来源的白细胞介素-10没有明显作用；然而，尽管在该模型中B细胞在淋巴组织白细胞介素-10产生中占主导地位，但髓样细胞在血液和肝脏中占主导地位。这些数据表明，B细胞是淋巴组织中反向调节性白细胞介素-10产生的一个未被充分认识的来源，为测试B细胞来源的白细胞介素-10在感染性和炎症性疾病中的生物学作用提供了明确的理论依据，并强调了细胞类型特异性基因敲除在免疫反向调节机制研究中的实用性。
