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

描述(由申请人提供)：最近发现的细胞因子IL-21增强了抗CD3介导的CD8+T细胞的激活。然而，IL-21对肿瘤抗原诱导的CD8+T细胞反应的影响尚不清楚。这项建议的目标是了解IL-21对肿瘤抗原特异性CD8+T细胞反应的潜在分子和细胞机制，并利用这些信息产生有效的T细胞用于癌症的过继细胞治疗。初步研究表明，IL-21可促进体内肿瘤抗原特异性CD8+T细胞的活化、增殖、分化和维持。IL-21调节初始CD8+T细胞反应的能力被证实。在体外系统中，TCR转基因CD8+T细胞(OT-I)对IL-21治疗的分子和细胞反应进行了评估。通过扩大这些研究，我们将检验IL-21治疗将产生大量长寿效应CD8+T细胞并促进对癌症的过继免疫的假设。提出了四个具体目标。在AIM 1中，我们将测试IL-21如何在抗原刺激下促进幼稚和失活的OT-I T细胞的激活和增殖，并确定STAT1、STAT3和STAT5在IL-21效应中的作用。I型细胞因子的表达和细胞毒性等效应功能的产生对肿瘤细胞的免疫控制至关重要。在目标2中，我们将通过阐述STAT1、STAT3和STAT5在OT-I效应器发育中的特定作用，确定IL-21如何促进未成熟和失活的OT-I T细胞的分化。免疫记忆是大多数癌症免疫治疗的理想目标。在目标3中，我们将测试IL-21在OT-I T细胞中产生记忆的能力，并确定STAT1、STAT3和/或STAT5在记忆形成中的作用。最后，在目标4中，我们将利用这些信息来测试IL-21单独或与细胞因子(如IL-15和/或IL-12)一起产生OT-I T细胞的有效性，这些T细胞通过过继治疗而对已确立的癌症无效。这些研究提供的见解可能会开发出合理使用IL-21单独或与其他细胞因子联合用于癌症、传染病、自身免疫和移植的治疗。

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.