Acquisition of Signal Information for Immune Surveillance and Determination of Immune Responses

我们旨在阐明免疫识别信息的获取和免疫应答的调控机制。树突状细胞（DC）作为免疫监视的核心机制，首先在感染时识别病原体，然后激活先天免疫，进而诱导抗原特异性识别和T细胞的激活。在本项目中，我们已经阐明了IRAK-4作为先天免疫信号中枢调节丝氨酸/苏氨酸激酶，在T细胞活化中作为适应性免疫的中枢反应也起着关键作用。在irak -4缺陷小鼠中，LCMV感染后CD8+ T细胞的增殖和细胞毒功能受损。我们通过T细胞转移实验分析了受损反应是否归因于dc或T细胞先天反应的缺陷，并发现T细胞激活在MHC I类和ii类限制性反应中都受损。事实上，我们不仅发现体内T细胞反应，而且还发现体外反应，包括同种异体反应、超抗原反应和抗tcr刺激反应。通过分析缺陷信号通路，特别是NF- at或NF-κB激活通路，我们发现NF-κB激活被抑制，PKCθ磷酸化受损似乎是导致NF-κB激活缺陷的原因。这些结果表明IRAK-4通过引导NF-κB激活在TCR激活信号中起关键作用。我们进一步分析了IRAK-4介导的NF-κB特异性激活机制，发现IRAK-4在过表达系统中与ZAP-70存在关联。IRAK-4似乎与ZAP-70一起在刺激时被募集到TCR附近，并参与激活调节。我们的研究结果表明，IRAK-4在先天免疫和获得性免疫中对NF-κB的激活都很重要，这表明IRAK-4对NF-κB的激活在系统发育过程中是保守的。

We aimed to clarify the mechanism on the acquisition of the information of immune recognition and regulation of immune responses. As the central mechanism of immune surveillance, dendritic cells (DC) first recognize pathogens upon infection, and then innate immunity is activated, which in turn induces antigen-specific recognition and activation of T cells. In this project, we have clarified that IRAK-4, a central regulatory serin/threonine kinase in innate immune signaling, plays also a critical role in T cell activation as the central response in the adaptive immunity. In IRAK-4-deficient mice, proliferation and cytotoxic function of CD8+ T cells were impaired upon LCMV infection. We analyzed whether the impaired response was attributed to the defects in innate response by DCs or T cells by using T cell transfer experiments, and found that T cell activation was impaired in both MHC class I and II-restricted responses. Indeed, we found that not only in vivo T cell responses but also in vitro responses including allogenic responses, super-antigen responses, and responses upon anti-TCR stimulation. By analyzing the defective signaling pathways, particularly NF-AT or NF-κB activation pathways, we found that NF-κB activation was suppressed and impaired phosphorylation of PKCθ appeared to be responsible for the defective NF-κB activation. These results indicate that IRAK-4 plays a critical role in TCR activation signals by directing towards NF-κB activation. We further analyzed the mechanism of IRAK-4-mediated NF-κB specific activation, and found that IRAK-4 associates with ZAP-70 in the over-expression system. IRAK-4 appears to be recruited together with ZAP-70 to the vicinity of TCR upon stimulation, and is involved in activation regulation. Our result that IRAK-4 is important for NF-KB activation in both innate and acquired immunities suggests that NF-κB activation by IRAK-4 has been conserved through phylogenic development.