Antigen-Specific CD8+ T Cell Responses by IL-21

IL-21 产生的抗原特异性 CD8 T 细胞反应

• 批准号: 6711245
• 负责人: Protul Shrikant
• 金额: $ 27.04万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-13 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711245
• 关键词: DNA binding protein; animal genetic material tag; cell line; cell mediated lymphocytolysis test; combination cancer therapy; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; genetic transduction; genetically modified animals; immunologic memory; immunomagnetic separation; immunoprecipitation; interleukin 12; interleukin 15; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; passive immunization; synthetic tumor antigen; tumor infiltrating lymphocyte; western blottings

DESCRIPTION (provided by applicant): The recently identified cytokine IL-21 augments anti-CD3 mediated CD8+ T cell activation. However, the effect of IL-21 on tumor-antigen induced CD8+ T cell responses remains unknown. The goals of this proposal are to understand the molecular and cellular mechanisms underlying the effects of IL-21 on tumor antigen-specific CD8+ T cell responses and utilize this information to generate effective T cells for adoptive cellular therapy of cancer. The preliminary characterizations suggest that IL-21 enhances activation, proliferation, differentiation and sustenance of tumor antigen specific CD8+ T cell responses in vivo. The ability of IL-21 to regulate naive CD8+ T cell responses was confirmed using an in vitro system in which TCR transgenic CD8+ T cells (OT-I) are evaluated for their molecular and cellular response to IL-21 treatment. By extending these investigations we will test the hypothesis that IL-21 treatment will generate large numbers of long-lived effector CD8+ T cells and promote adoptive immunity against cancer. Four specific aims are proposed. In aim1, we will test how IL-21 augments naive and anergized OT-I T cell activation and proliferation upon antigen stimulation, the role for STAT1, STAT3 and STAT5 in the IL-21 effect will be determined. The generation of effector functions such as type 1 cytokine expression and cytotoxicity are critical for immunological control of tumor cells. In aim 2, we will determine how IL-21 promotes differentiation in nave and anergized OT-I T cells, by addressing the specific role of STAT1, STAT3 and STAT5 in OT-I effector development. Immunological memory is a desirable objective for most cancer immunotherapies. In aim 3, we will test the ability of IL-21 to generate memory in OT-I T cells and establish a role for STAT1, STAT3 and/or STAT5 in the memory formation. Finally, in aim 4, we will utilize this information to test the effectiveness of IL-21 alone or in combination with cytokines such as IL-15 and/or IL-12 in producing OT-I T cells that result inefficacy against established cancer by adoptive therapy. The insights provided by these investigations are likely to develop rational use of IL-21 alone or in combination with other cytokines for the therapy of cancer, infectious diseases, autoimmunity and transplantation.

描述（由申请人提供）：最近确定的细胞因子IL-21增强了抗CD3介导的CD8+ T细胞激活。但是，IL-21对肿瘤抗原诱导的CD8+ T细胞反应的影响尚不清楚。该提案的目标是了解IL-21对肿瘤抗原特异性CD8+ T细胞反应的影响的基础的分子和细胞机制，并利用该信息来生成有效的T细胞来产生癌症的过养细胞治疗。初步特征表明，IL-21增强了体内肿瘤抗原特异性CD8+ T细胞反应的激活，增殖，分化和维持。使用体外系统证实了IL-21调节幼稚CD8+ T细胞反应的能力，在该系统中，评估了TCR转基因CD8+ T细胞（OT-I）的分子和细胞对IL-21治疗的分子反应。通过扩展这些研究，我们将检验以下假设：IL-21治疗将产生大量寿命效应子CD8+ T细胞并促进对癌症的收养免疫力。提出了四个具体目标。在AIM1中，我们将测试IL-21在抗原刺激时如何增强幼稚和渗透的OT-IT细胞激活和增殖，STAT1，STAT3和Stat5在IL-21效应中的作用将被确定。效应子功能（例如1型细胞因子表达和细胞毒性）的产生对于肿瘤细胞的免疫控制至关重要。在AIM 2中，我们将通过解决STAT1，STAT3和STAT5在OT-I效应子开发中的特定作用来确定IL-21如何促进NA VE和渗入OT-I T细胞的分化。免疫记忆是大多数癌症免疫疗法的理想目标。在AIM 3中，我们将测试IL-21在OT-I T细胞中生成内存的能力，并在内存形成中为STAT1，STAT3和/或STAT5建立角色。最后，在AIM 4中，我们将利用此信息单独测试IL-21或与细胞因子（例如IL-15和/或IL-12）结合的有效性，以产生通过收养治疗对既定癌症的效率低下的OT-I T细胞。这些研究提供的见解很可能单独形成IL-21或与其他细胞因子联合使用癌症治疗，传染病，自身免疫性和移植。