TCR-BINDING PEPTIDES FROM COMBINATORIAL LIBRARIES

免疫学家在增强和修改免疫系统以诱导免疫反应方面已经变得很熟练。然而，一旦免疫系统针对特定抗原启动，就很难特异性地阻止这种反应。简而言之，我们已经非常熟练地开启了免疫系统，但还在学习如何关闭它。T细胞，尤其是辅助性T细胞，分泌的细胞因子对其他免疫细胞的表型和活性有很大的影响。T细胞受体（Tcrs）负责T细胞的特异性，并识别各种外来和自身抗原。尽管教条指出T细胞必须识别与MHC结合的肽抗原，但我们已经证明Tcrs也可以识别未与MHC结合的游离肽。本提案的具体目的是从组合肽库中鉴定tcr结合的非mhc限制性肽，并评估它们对T细胞的影响，如能量、增殖或细胞因子分泌的改变。我们假设T细胞的功能可以通过与T细胞结合的游离的tcr特异性肽来控制。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不良细胞因子的分泌。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细胞产生生物效应。我们建议开发肽配体面板，以调节T细胞功能为目标，对T细胞产生可预测和可重复的影响。这种方法的一个主要优点是它不受MHC结合基序的限制，这意味着不需要首先确定病理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.