Akkaya Munir, Akkaya Billur, Miozzo Pietro, Rawat Mukul, Pena Mirna, Sheehan Patrick W, Kim Ann S, Kamenyeva Olena, Kabat Juraj, Bolland Silvia, Chaturvedi Akanksha, Pierce Susan K
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 2017 Aug 1;199(3):931-940. doi: 10.4049/jimmunol.1700348. Epub 2017 Jun 26.
B cells express the innate receptor, TLR9, which signals in response to unmethylated CpG sequences in microbial DNA. Of the two major classes of CpG-containing oligonucleotides, CpG-A appears restricted to inducing type 1 IFN in innate immune cells and CpG-B to activating B cells to proliferate and produce Abs and inflammatory cytokines. Although CpGs are candidates for adjuvants to boost innate and adaptive immunity, our understanding of the effect of CpG-A and CpG-B on B cell responses is incomplete. In this study we show that both CpG-B and CpG-A activated B cells in vitro to proliferate, secrete Abs and IL-6, and that neither CpG-B nor CpG-A alone induced type 1 IFN production. However, when incorporated into the cationic lipid, DOTAP, CpG-A, but not CpG-B, induced a type 1 IFN response in B cells in vitro and in vivo. We provide evidence that differences in the function of CpG-A and CpG-B may be related to their intracellular trafficking in B cells. These findings fill an important gap in our understanding of the B cell response to CpGs, with implications for the use of CpG-A and CpG-B as immunomodulators.
B细胞表达天然受体TLR9，该受体可响应微生物DNA中的未甲基化CpG序列发出信号。在含CpG的两类主要寡核苷酸中，CpG-A似乎仅限于在天然免疫细胞中诱导1型干扰素，而CpG-B则能激活B细胞增殖并产生抗体和炎性细胞因子。尽管CpG是增强天然免疫和适应性免疫的佐剂候选物，但我们对CpG-A和CpG-B对B细胞反应的影响的了解并不完整。在本研究中，我们表明CpG-B和CpG-A在体外均能激活B细胞增殖、分泌抗体和IL-6，且单独的CpG-B和CpG-A均不能诱导1型干扰素的产生。然而，当与阳离子脂质DOTAP结合时，CpG-A而非CpG-B能在体外和体内诱导B细胞产生1型干扰素反应。我们提供的证据表明，CpG-A和CpG-B功能上的差异可能与其在B细胞内的转运有关。这些发现填补了我们对B细胞对CpG反应理解中的一个重要空白，对将CpG-A和CpG-B用作免疫调节剂具有启示意义。
