Transcriptional regulation of vaccine-elicited and infection-elicited CD8+ T cell responses

项目摘要 Toll样受体(TLR)和CD40激动剂同时存在时的抗原免疫 (TLR/CD40联合免疫)可诱导抗原特异性CD8+T细胞的旺盛增殖，即 指数级大于任何一种激动剂单独引起的反应。不仅是初级免疫 对这种疫苗的反应强劲，它还形成了长寿的CD8+T细胞记忆，可以预防未来 感染挑战即使在没有CD4+T细胞的情况下也是如此。这一点最近在非人类身上得到了证实。 在灵长类动物中，疫苗产生的反应比对典型病毒载体的反应要强得多。 鉴于这一疫苗佐剂平台的效力和临床潜力，我们必须了解其 分子和细胞的机械基础。我们发现T细胞对佐剂的反应 亚基疫苗的接种出人意料地完全依赖于细胞因子IL-27和IL-15。这是 令人惊讶的是，T细胞对感染性挑战的反应有增无减，甚至可以 升高(由于IL-27缺乏)，在缺乏这些细胞因子的情况下。最近，我们确定了 在疫苗接种过程中，转录因子IRF4的表达是IL-27/15信号的主要结果。IRF4是 充分证明了促进有氧糖基化作为T细胞的能量和生物量产生的来源 在最初的免疫反应中。然而，我们发现，对疫苗接种有反应的T细胞几乎 独家利用线粒体呼吸，一种新陈代谢应该只被幼稚和 记忆T细胞和NOT细胞经历了戏剧性的增殖爆发的初级反应。因此，IRF4 似乎促进了T细胞中非常不同类型的代谢程序，这取决于它是否 曾遇到亚单位疫苗或感染的炎性环境。这些和其他 观察使我们得出结论，强健的亚单位疫苗诱导的免疫背后的规则似乎是 与那些引导传染病反应的方法有很大的不同。这项提案将使用尖端的方法 以及充分理解这种差异的性质并将测试i)IL-27和IL-15如何影响 下游转录因子网络，II)这些转录元件如何与疫苗结合-vs. 感染驱动的T细胞激活和扩增程序，以及III)早期T-DC相互作用可能 同时影响转录因子的表达和下游对代谢编程的影响 初级CD8+T细胞应答。

Project Summary Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. Not only is the primary immune response to this vaccination robust, it also forms long lived, CD8+ T cell memory that can protect against future infectious challenge even in the absence of CD4+ T cells. This has been recently verified in non-human primates, where the vaccine produced responses exponentially stronger than responses to typical viral vectors. Given the potency and clinical potential for this vaccine adjuvant platform, it is critical that we understand its molecular and cellular mechanistic underpinnings. We made the discovery that T cell responses to adjuvanted subunit vaccinations were unexpectedly and completely dependent on the cytokines IL-27 and IL-15. This was surprising because the T cell response to an infectious challenge proceeds unabated, and can even be elevated (for IL-27 deficiency), in the absence of these cytokines. More recently, we have identified the expression of the transcription factor IRF4 as a major result of IL-27/15 signaling during vaccination. IRF4 is well documented to facilitate aerobic glycosylation as the source of energy and biomass generation for T cells during the primary immune response. However, we found that T cells responding to vaccination almost exclusively utilized mitochondrial respiration, a metabolism that is supposed to be used only by naïve and memory T cells and not cells undergoing the dramatic proliferative burst of the primary response. Thus, IRF4 appears to be facilitating very different kinds of metabolic programs in a T cell depending on whether or not it has been encountered the inflammatory environment of a subunit vaccine or of an infection. These and other observations make us conclude that the rules behind robust subunit vaccine-elicited immunity appear to be substantially different than those guiding infectious responses. This proposal will use cutting edge methods and approaches to fully understand the nature of this difference and will test i) how IL-27 and IL-15 influence downstream transcription factor networks, ii) how these transcriptional elements are tied into vaccine- vs. infection-driven programs of T cell activation and expansion, and iii) how the earliest T-DC interactions might influence both transcription factor expression and downstream influence on metabolic programming of the primary CD8+ T cell response.