Antigen specificity, suppressive mechanism & regulation of CD4+ regulatory T cell

描述（由申请人提供）：最近的研究表明，CD4+调节性T （Treg）细胞可以抑制最佳抗肿瘤免疫所需的CD4+和CD8+效应细胞反应。这些观察结果可以解释，至少部分解释，为什么用癌症疫苗（包括MHC I类限制性肿瘤抗原或肽）诱导强烈和持久的抗肿瘤反应的尝试在很大程度上是不成功的。该项目的目标是开发新的策略，将CD4+ Treg细胞介导的抑制性免疫反应的平衡转变为有效的T辅助免疫反应，从而产生持久的抗肿瘤免疫，最终破坏肿瘤。其基本原理是肿瘤细胞不仅通过分泌白细胞介素(IL)-10和tgf - β提供抑制环境，而且还通过呈现肿瘤相关或特异性配体在局部肿瘤部位积极招募和激活CD4+ Treg细胞。这些肿瘤抗原特异性CD4+ Treg细胞反过来对有效的T细胞抗癌反应发挥有效的抑制作用。申请人实验室的研究已经从癌症患者的临床样本中建立了几种抗原特异性CD4+ Treg细胞系和克隆。这些独特的细胞，加上一些新开发的技术，应该能够识别肿瘤特异性CD4+ Treg细胞的重要配体，从而允许对一个新概念进行更严格的测试-将动态平衡从抑制性CD4+ Treg细胞转移到有利于t辅助介导的抗肿瘤反应的环境可能会提高癌症免疫治疗的有效性。为了验证我们的新概念和假设，我们提出了三个具体的研究目标：(1)利用已建立的CD4+ Treg细胞系/克隆鉴定编码这些细胞配体的基因，然后表征蛋白质产物的自然特性；(2)剖析CD4+ Treg细胞的免疫抑制机制和调控，获得动物模型假设检验所需的关键信息；(3)利用TCR转基因小鼠和B16肿瘤模型在体内调节或逆转CD4+ Treg细胞的抑制功能。这项为期5年的研究提出的策略将应用于不同的肿瘤抗原，在不同的动物模型中进行测试，以验证CD4+ Treg/效应细胞平衡的改变确实有助于更有效的癌症免疫治疗。这些研究的积极成果将为治疗癌症患者，也许还有传染性和自身免疫性疾病开辟新的机会。

DESCRIPTION (provided by applicant): Recent studies suggest that CD4+ regulatory T (Treg) cells can suppress the CD4+ and CD8+ effector cell responses needed for optimal antitumor immunity. These observations may explain, at least in part, why attempts to elicit strong and durable antitumor responses with cancer vaccines (comprising MHC class I- restricted tumor antigens or peptides) have been largely unsuccessful. The goals of this project are to develop new strategies to shift the balance from CD4+ Treg cell-mediated suppressive immune response toward effective T helper immune response, thus generating long-lasting antitumor immunity for the ultimate tumor destruction. The underlying rationale is that tumor cells not only provide a suppressive environment by secreting interleukin (IL)-10 and TGF-beta, but also actively recruit and activate CD4+ Treg cells at local tumor sites by presenting tumor-associated or -specific ligands. These tumor antigen-specific CD4+ Treg cells, in turn, exert potent suppressive effects on effective T cell responses against cancer. Research in the applicant's laboratory has established several antigen-specific CD4+ Treg cell lines and clones from clinical samples taken from cancer patients. These unique cells, together with several newly developed technologies, should enable identification of important ligands for tumor-specific CD4+ Treg cells, permitting in turn more rigorous testing of a novel concept--that shifting the dynamic balance from suppressive CD4+ Treg cells to a milieu favoring T-helper-mediated antitumor responses may boost the effectiveness of cancer immunotherapy. To test our novel concept and hypothesis, we proposes three specific research aims: (1) use established CD4+ Treg cell lines/clones to identify genes encoding the ligands of these cells and then characterize the natural properties of the protein products; (2) dissect the immunosuppressive mechanisms and regulation of the CD4+ Treg cells to gain critical information needed for hypothesis testing in animal models; (3) use TCR transgenic mice and the B16 tumor model to modulate or reverse the suppressive function of CD4+ Treg cells in vivo. The strategies emerging from this 5-year proposal will be applied to different tumor antigens, tested in different animal models, to verify that a shift in the CD4+ Treg/effector cell balance is indeed conducive to more effective cancer immunotherapy. A positive outcome of these studies would open new opportunities for treating cancer patients and perhaps infectious and autoimmune diseases as well.