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

描述（由申请人提供）：最近鉴定的细胞因子IL-21增强抗CD 3介导的CD 8 + T细胞活化。然而，IL-21对肿瘤抗原诱导的CD 8 + T细胞应答的作用仍然未知。该提案的目标是了解IL-21对肿瘤抗原特异性CD 8 + T细胞应答的作用的分子和细胞机制，并利用这些信息产生用于癌症过继细胞治疗的有效T细胞。初步的表征表明，IL-21在体内增强肿瘤抗原特异性CD 8 + T细胞应答的活化、增殖、分化和维持。使用体外系统证实IL-21调节初始CD 8 + T细胞应答的能力，其中评估TCR转基因CD 8 + T细胞（OT-I）对IL-21处理的分子和细胞应答。通过扩展这些研究，我们将检验IL-21治疗将产生大量长寿命效应CD 8 + T细胞并促进针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如何在抗原刺激后增强幼稚和无活力OT-I T细胞活化和增殖，将确定STAT 1、STAT 3和STAT 5在IL-21效应中的作用。效应子功能如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。在目标2中，我们将确定IL-21是如何促进NA细胞分化的，通过阐明STAT 1、STAT 3和STAT 5在OT-I效应子发育中的特异性作用，免疫记忆是大多数癌症免疫疗法的理想目标。在目的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STAT 1、STAT 3和/或STAT 5在记忆形成中的作用。最后，在目标4中，我们将利用该信息来测试IL-21单独或与细胞因子如IL-15和/或IL-12组合在产生OT-I T细胞中的有效性，所述OT-I T细胞通过过继疗法导致对已建立的癌症无效。这些研究所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治疗癌症，感染性疾病，自身免疫和移植。

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.