Innate DC Govern TH Polarization through the Novel Regulator AIMp1

摘要 在活病毒疫苗接种之外，无法产生有效的细胞介导免疫的情况仍在继续 对于免疫功能低下的个体接种疫苗是一个普遍的临床问题，细胞介导的预防 对于没有活疫苗的病毒性疾病，至关重要的是，产生持久的抗肿瘤免疫 回应。细胞介导的免疫是由树突状细胞(DC)启动的，树突状细胞是天然免疫的关键谱系， 是免疫的先天和适应性手臂之间的主要接触点和串音点。 系统。对病原体成功响应需要DC检测和整合广泛的环境 提示精确控制关键的下游反应，特别是T辅助(TH)细胞极化。许多这样的人 线索以及检测和整合的机制仍有待了解。在本提案中，我们将 询问新出现但得到很好支持的假说，即新型调控因子AIMp1的DC表达驱动 TH1细胞免疫的生理性传播。这一假设建立在广泛而严谨的数据基础上。 证明AIMp1的遗传消融在TH1极化方面产生了明显更深刻的缺陷 而不是IL-12或IL-12R缺陷小鼠的特征。AIMp1基因敲除小鼠失去装载 针对流感的适应性免疫反应，对通常亚致命的挑战表现出完全致命性， 感染后肺内几乎所有分泌干扰素-g的T细胞都丧失，导致HA特异性IgG2a产生不足 第15天：AIMp1-/-动物也表现出完全丧失了可被收养挽救的抗肿瘤免疫 传输野生型DC。从机制上讲，这些数据表明这些缺陷是由于p38MAPK激活缺陷造成的 在AIMp1-/-DC中，AP-1异二聚化下游失调。AIMp1与人类的直接相关性 通过对9000例原发人类肿瘤标本进行泛癌TCGA生物信息学分析，验证了疾病的有效性。 PLES显示，在AIMp1水平升高的患者中，患者意外获得了70%的生存优势 原发肿瘤。在这个数据集中，AIMp1的高表达与激活的DC基因高度相关 签名和TH1免疫档案。值得注意的是，这一生存优势并未在 其中原发肿瘤IL-12A(P35)高表达。这些数据表明一个未被识别的 然而，DC表达的AIMp1在适应性TH1治理中扮演着不可或缺的角色，并为 本研究证实一种新的调控因子对TH1诱导的整合和转导是必不可少的 DC中的信号将改变目前理解TH1免疫信号的范式。其作用机制 AIMp1通过什么来调控细胞免疫，将取决于三个特定目标的完成。在……里面 目的定义体内树突状细胞亚群(S)，其AIMp1功能对TH1免疫的传播起关键作用。 在AIM II中，我们将定义AIMp1与DC调节信号级联的接口方式。在AIM III我们将定义DC人群中AIMp1的条件性缺失所导致的效应细胞功能缺陷。在……里面 所有目标，AIMp1缺乏和IL-12缺乏之间的区别将在适当的情况下描述。

Abstract The inability to generate effective cell-mediated immunity outside the context of live virus vaccination continues to be a pervasive clinical problem for vaccination of immunocompromised individuals, cell-mediated prophylaxis of viral diseases for which no live vaccines exist, and critically, the generation of durable antitumor immune responses. Cell mediated immunity is initiated by dendritic cells (DC), a critical lineage of innate immunity that serves as the principal point of contact and crosstalk between the innate and adaptive arms of the immune system. Successful response to pathogen requires that DC detect and integrate a broad array of environmental cues to exact control over critical downstream responses, particularly T-helper (TH) cell polarization. Many such cues, as well as mechanisms of detection and integration, remain to be understood. In this proposal we will interrogate the emerging but well-supported hypothesis that DC expression of the novel regulator AIMp1 drives physiologic propagation of TH1 cellular immunity. This hypothesis is based upon extensive and rigorous data demonstrating that genetic ablation of AIMp1 produces deficits in TH1 polarization significantly more profound than those characterized in IL-12 or IL-12R-deficient mice. AIMp1 knockout mice lose the ability to mount an adaptive immune response against influenza, exhibiting complete lethality to a normally sublethal challenge, deficient HA-specific IgG2a production, and loss of nearly all IFN-g-secreting T-cells in the lung by post-infection day 15. AIMp1-/- animals also exhibited complete loss of antitumor immunity that could be rescued by adoptive transfer of wildtype DC. Mechanistically, the data suggest these deficits are due to defective p38MAPK activation in AIMp1-/- DC with downstream dysregulation of AP-1 heterodimerization. Direct relevance of AIMp1 to human disease was validated through a pan-cancer TCGA bioinformatics analysis of 9,000 primary human tumor sam- ples, revealing an unexpected 70% survival advantage among patients expressing elevated levels of AIMp1 in the primary tumor. In this dataset, elevated AIMp1 expression was highly correlated with an activated DC gene signature and TH1 immune profile. Strikingly, this survival advantage was not recapitulated among patients in which the primary tumor exhibited high levels of IL-12A (p35) expression. These data suggest an unrecognized yet indispensable role for DC-expressed AIMp1 in adaptive TH1 governance and provide a cogent rationale for this study: confirmation that a novel regulatory factor is essential for integration and transduction of TH1-inducing signals in DC will alter the paradigm by which TH1 immune signaling is presently understood. The mechanisms through which AIMp1 governs cellular immunity will be determined by the completion of three specific aims. In aim I we will define the in vivo DC subset(s) for which AIMp1 function is critical to propagation of TH1 immunity. In aim II we will define the manner by which AIMp1 interfaces with the DC regulatory signaling cascade. In aim III we will define deficits in effector cell function that result from conditional loss of AIMp1 in DC populations. In all aims, differences between AIMp1-deficiency and IL-12 deficiency will be characterized where appropriate.