Molecular mechanisms of T cell anergy

描述（由申请人提供）：区分自我与非自我的能力对于维持适当的免疫稳态至关重要。大多数自反应性T细胞通过负选择在胸腺中被消除；然而，一些携带识别自身蛋白的T细胞受体的细胞仍可能逃脱胸腺选择并作为成熟T细胞进入外周系统。为了避免自身免疫，这些细胞必须灭活。能量是确保适当控制自身反应性T细胞的机制之一。CD4+ T细胞在次优或部分刺激后变得无能或对抗原无反应。在辅助性T细胞中，能量是由一组特定的能量相关基因的nfat依赖性表达产生的，这些基因编码抑制TCR信号传导和抑制细胞因子转录的蛋白质。一些报道也发现T细胞能量是恶性肿瘤诱导免疫逃避的重要机制。尽管有证据表明T细胞能量可能在预防自身免疫性疾病和促进癌细胞逃避免疫反应的能力方面发挥关键作用，但T细胞能量在体内调节T细胞反应中发挥的确切作用仍有待充分解决。根据这一建议，我们打算进一步表征调节T细胞能量诱导的转录机制，并利用这些知识来评估T细胞能量在两个不同过程中的具体作用：维持自我耐受性和肿瘤诱导的免疫耐受性；最后是3。制定一种策略来调节T细胞能量的诱导，并评估其作为治疗工具的可能性。详细了解T细胞能量的调节和生理作用，以及确定特异性调节这一过程的新靶点，将为设计治疗自身免疫性疾病的策略、防止移植物排斥反应或激活T细胞对肿瘤细胞或慢性感染的反应提供有价值的信息。

DESCRIPTION (provided by applicant): The ability to distinguish self from non-self is essential in maintaining proper immune homeostasis. Most self-reactive T cells are eliminated in the thymus through negative selection; however some cells bearing T cell receptors that recognize self-proteins may still escape thymic selection and enter the peripheral system as mature T cells. To avoid autoimmunity, those cells must be inactivated. Anergy is of one of the mechanisms that ensure proper control of self-reactive T cells. CD4+ T cells become anergic or unresponsive to antigen following suboptimal or partial stimulation. In T helper cells, anergy is established as a consequence of the NFAT-dependent expression of a specific set of anergy-associated genes, which encode proteins that dampen TCR signaling and inhibit cytokine transcription. Several reports have also identified T cell anergy as an important mechanism of immune evasion induced by malignant tumors. Although evidence suggests that T cell anergy may play a key role in preventing autoimmune disease and facilitating the ability of cancer cells to evade immune responses, the precise role that T cell anergy plays in regulating T cell responses in vivo remains yet to be fully addressed. With this proposal we intend to further characterize the transcriptional mechanisms that regulate the induction of T cell anergy and use that knowledge to evaluate the specific role of T cell anergy in two different processes: maintenance of self tolerance and tumor-induced immune tolerance; and finally 3. Develop a strategy to regulate the induction of T cell anergy and evaluate its possible use a therapeutic tool. A detailed understanding of the regulation and the physiological role of T cell anergy and the identification of new targets to specifically modulate this process should provide valuable information to design strategies for the treatment of autoimmune diseases, to prevent graft rejection or to activate T cell responses against tumor cells or during chronic infections. PUBLIC HEALTH RELEVANCE: Inactivation of self-reactive T cells has been identified as an important mechanism in the control of immune reactions against our own tissues. This process, termed anergy, is also crucial to understand how chronic infections and cancer cells can evade effective immune responses. The aim of this project is to characterize the molecular mechanisms that control how T cells anergy is established and, based on that knowledge, develop potential therapeutic strategies that may help enhance T cell responses against cancer cells and chronic pathogens.