TCR-BINDING PEPTIDES FROM COMBINATORIAL LIBRARIES

免疫学家已经熟练地增强和修饰免疫系统以诱导免疫应答。 然而，一旦免疫系统已经针对特定抗原启动，就很难特异性地停止这种反应。 简而言之，我们已经非常擅长打开免疫系统，但只是学习如何关闭它。 T细胞，特别是T辅助细胞，分泌强烈影响其他免疫细胞的表型和活性的细胞因子。 T细胞受体（Tcrs）负责T细胞的特异性，并识别各种各样的外来和自身抗原。 尽管理论上T细胞必须识别与MHC结合的肽抗原，但我们已经证明Tcrs也能识别未与MHC结合的游离肽。 该提案的具体目的是从组合肽文库中鉴定TCR结合的非MHC限制性肽，并评估它们在T细胞中引起的效应，例如无反应性、增殖或改变的细胞因子分泌。 我们假设，T细胞功能可以被控制，以治疗优势与游离的，TCR特异性肽结合T细胞。 介导这些活性的肽可用于控制许多自身免疫性疾病中的病理性T细胞或一些感染性疾病中的不期望的细胞因子分泌。 该项目的长期目标是了解我们鉴定的肽如何以及为什么对T细胞产生生物学效应。我们建议开发一组肽配体，这些肽配体对T细胞产生可预测和可重复的作用，目的是调节T细胞功能。 这种方法的主要优点是它不受MHC结合基序的限制，这意味着不需要首先定义病理性T细胞所针对的特定蛋白质或肽。

Immunologists have become skilled at enhancing and modifying the immune system to induce an immune response. However, once the immune system has been primed against a specific antigen, it is very difficult to specifically stop that response. In short, we have become very adept at turning the immune system on but are just learning how to turn it off. T cells, especially T helper cells, secrete cytokines which strongly influence the phenotypes and activity of other immune cells. T cell receptors (Tcrs) are responsible for the specificity of T cells and recognize a diverse array of foreign and self antigens. Although dogma states that T cells must recognize peptide antigens bound to MHC, we have shown that Tcrs will also recognize free peptides not bound to MHC. The specific aims of this proposal are to identify Tcr-binding, non-MHC restricted peptides from combinatorial peptide libraries and evaluate the effects they elicit in T cells such as anergy, proliferation or altered cytokine secretion. We hypothesize that T cell function can be controlled to therapeutic advantage with free, Tcr-specific peptides upon binding to T cells. Peptides that mediate these activities could be useful in controlling pathologic T cells in many autoimmune diseases or undesirable cytokine secretion in some infectious diseases. The long-term objectives of this project are to understand how and why the peptides we identify exert biological effects on T cells. We propose to develop panels of peptide ligands that elicit predictable and reproducible effects on T cells with the objective of modulating T cell function. A major strength of this approach is that it is not constrained by MHC binding motifs which means that it is not necessary to first define the specific protein or peptide against which a pathologic T cell is directed.