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细胞活化。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。本提案的目标是了解IL-21对肿瘤抗原特异性CD8+ T细胞反应影响的分子和细胞机制，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。初步表征表明，IL-21在体内可促进肿瘤抗原特异性CD8+ T细胞的活化、增殖、分化和维持。IL-21调节幼稚CD8+ T细胞反应的能力通过体外系统得到证实，该系统评估了TCR转基因CD8+ T细胞（OT-I）对IL-21处理的分子和细胞反应。通过扩展这些研究，我们将验证IL-21治疗将产生大量长寿命的效应CD8+ T细胞并促进对癌症的过继性免疫的假设。提出了四个具体目标。在目的1中，我们将测试IL-21如何在抗原刺激下增强幼稚和失能的OT-I T细胞的活化和增殖，STAT1、STAT3和STAT5在IL-21效应中的作用将被确定。1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，我们将通过解决STAT1， STAT3和STAT5在OT-I效应物发育中的特定作用，确定IL-21如何促进nave和无能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联合产生OT-I - T细胞的有效性，这些细胞通过过继治疗对已建立的癌症无效。这些研究提供的见解可能有助于合理使用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.