CYTOKINE-MEDIATED T CELL ACTIVATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 病毒特异性CD 8 + T细胞通常通过严格调节其细胞因子产生并响应于直接抗原接触而打开、关闭和再次打开细胞因子分泌来避免引起严重的免疫病理学。 相比之下，白细胞介素-12（IL-12）和白细胞介素-18（IL-18）代表两种有效的炎性细胞因子，其在不存在直接抗原接触的情况下触发活化的T细胞产生干扰素-γ（IFNg）。 虽然已知活化的CD 8 + T细胞对IL-12/IL-18刺激有反应，但这些细胞因子对长期静息记忆T细胞的影响在很大程度上是未知的，这代表了我们对这一现象的理解存在重大差距。在我们提出的研究中，我们将比较和对比效应和记忆T细胞在以下方面的特定特异性：1）细胞因子产生，2）细胞溶解活性，3）增殖，和4）用IL-12和IL-18刺激后的整体基因表达。 这些信息对于理解IL-12/IL-18分泌如何被感染细胞用作内在的“危险”信号以触发附近抗原经历的T细胞的抗微生物免疫应答而不需要直接TcR刺激将是重要的。 另一方面，这种抗原特异性的丧失似乎也在与继发性细菌感染和脓毒性休克相关的某些类型的T细胞介导的免疫病理学中发挥重要作用。 由于这些原因，对马槟榔碱介导的T细胞活化的透彻理解对于学习如何维持或增强适当的T细胞应答，同时减少T细胞相关的疾病症状至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Virus-specific CD8+ T cells often avoid causing severe immunopathology by strictly regulating their cytokine production and turning cytokine secretion on, off, and on again in response to direct antigen contact. In contrast, interleukin-12 (IL-12) and interleukin-18 (IL-18) represent two potent inflammatory cytokines that trigger interferon-gamma (IFNg) production by activated T cells in the absence of direct antigen contact. Although activated CD8+ T cells are known to respond to IL-12/IL-18 stimulation, the effects of these cytokines on long-term, resting memory T cells is largely unknown and represents a significant gap in our understanding of this phenomenon. In our proposed studies, we will compare and contrast effector and memory T cells of a defined specificity in terms of: 1) cytokine production, 2) cytolytic activity, 3) proliferation, and 4) global gene expression following stimulation with IL-12 and IL-18. This information will be important for understanding how IL-12/IL-18 secretion might be used by infected cells as an intrinsic "danger" signal to trigger antimicrobial immune responses by nearby antigen-experienced T cells without requiring direct TcR stimulation. On the other hand, this loss of antigen specificity also appears to play a substantial role in certain types of T cell-mediated immunopathology associated with secondary bacterial infections and septic shock. For these reasons, a thorough understanding of cytokine-mediated T cell activation is critical for learning how to maintain or augment appropriate T cell responses while at the same time decreasing T cell-associated symptoms of disease.