IL-6: an innate immune regulator for the plasticity of Tfh cells

描述（由申请人提供）：T滤泡辅助细胞（Tfh细胞）是一种新的效应细胞亚群，其特点是它们存在于生发中心，产生IL-21，并作为B细胞和抗体（IgG）产生的辅助细胞。然而，与其他辅助性T细胞亚群不同，Tfh细胞似乎存在一定程度的可塑性，因为它们没有完全投入并可能失去其表型，如果存在合适的环境，不同的效应细胞可以成为Tfh细胞。造成这种可塑性的因素尚不清楚。我们已经证明，IL-6是一种由许多先天免疫细胞和非造血细胞衍生的细胞因子，是诱导初始和记忆CD4 T细胞产生IL-21的必要和充分的独特因素。我们的初步研究表明，在激活效应Th1、Th2和Th17细胞的过程中，IL-6也能够促进IL-21的产生。我们还表明，IL-6通过间接作用于CD4 T细胞，诱导其IL-21的产生，以及这种IL-21作用于B细胞，从而增强抗体反应。我们提出IL-6是一种主要的先天免疫因子，它通过在CD4 T细胞中不完全承诺的调节性调节IL-21表达来促进Tfh细胞的可塑性，从而促进Ab的产生。我们还提出IL-6引起的可塑性是通过其对两个独立信号通路的作用介导的，1)STAT3，调节线粒体代谢，2)C/EBP2，提供IL-21的选择性表达。il -6介导的可塑性可能是先天免疫应答与CD4和B细胞应答整合的关键。我们将确定1)IL-6对Tfh细胞可塑性的贡献（目的1）；2)STAT3和C/EBP2转录因子对IL-6介导的CD4 Tfh细胞可塑性的贡献（目的2）；3)IL-6通过促进记忆性CD4 T细胞转变为Tfh细胞在保护性抗病毒记忆反应中的作用（目的3）。

DESCRIPTION (provided by applicant): T follicular helper cells (Tfh cells) are a new subset of effector cells characterized by their presence in germinal centers, the production of IL-21 and their essential role as helper of B cells and antibody (IgG) production. However, unlike other T helper subsets, a certain degree of plasticity seems to be present in Tfh cells since they are not fully committed and can lose their phenotype, and different effector cells can become Tfh cells if the right environment is present. The factor/s contributing to this plasticity remain unknown. We have shown that IL-6, a cytokine derived by a number of innate immune cells and non-hematopoietic cells, is a unique factor necessary and sufficient to induce IL-21 production in naove and memory CD4 T cells. Our preliminary studies indicate the IL-6 is also able to enhance IL-21 production during the activation of effector Th1, Th2 and Th17 cells. We have also shown that IL-6 enhances antibody responses by indirectly acting on CD4 T cells, inducing their IL-21 production, and this IL-21 acting on B cells. We propose that IL-6 is a major innate immune factor that contributes to the plasticity of Tfh cells and thereby Ab production by tonically regulating IL-21 expression in CD4 T cells without a full commitment. We also propose that the plasticity caused by IL-6 is mediated by its effect on two independent signaling pathways, 1) STAT3, modulating mitochondrial metabolism, and 2) C/EBP2, providing selective expression of IL-21. IL-6-mediated plasticity may be key in the integration of the innate immune response with CD4 and B cell responses. We will determine 1) the contribution of IL-6 to the plasticity of Tfh cells by tonically inducing IL-21 production in naive, effector and memory CD4 T cells (Aim 1), 2) the contribution of STAT3 and C/EBP2 transcription factors to the IL-6 mediated plasticity of CD4 Tfh cells (Aim 2), 3) the role of IL-6 in protective antiviral memory response by promoting memory CD4 T cells to become Tfh cells (Aim 3).