Role of CD91 and its ligands in immune response

摘要 热休克蛋白(HSP70)、热休克蛋白90(HSP90)和钙网织蛋白家族的热休克蛋白(HSPs)具有丰富的可溶性 引起强大免疫反应的细胞内蛋白质。这些回应包括 T细胞反应的先天和适应性两个方面的组成部分及其下调。 热休克蛋白在抗原提呈过程中伴侣多肽和内化受体的能力 细胞是它们引发免疫反应的两个关键属性。热休克蛋白在交叉中的关键作用 2005年还设想并演示了在T细胞反应期间启动抗原。 在这项应用中，我们的目标是(I)研究HSP受体CD91在交叉启动中的作用。 小鼠系统，(II)检测CD91α2-巨球蛋白的免疫原性机制 配体，内源性和人工地与各种多肽络合，以及(Iii)测试 血清2M水平对小鼠免疫应答能力的影响。 目的1：探讨热休克蛋白受体CD91在T细胞应答交叉激发中的作用。 A.确定表达RAP(CD91的竞争性抑制物)的细胞交叉存在的能力 抗原和启动有效的T细胞反应； B.CD91条件性基因敲除小鼠的建立及其免疫学特性 在这只鼠标中做出反应。 目的：探讨2M介导的免疫原性机制及其在临床上的应用。 癌症和传染病的免疫治疗。 A.研究？2M共刺激激活的机制； B.检查2M-肽复合体的细胞内转运和加工。 C.检测肿瘤衍生多肽与2M的络合物对肿瘤的预防和治疗作用； D.内源性形成的2M-肽复合体作为免疫原的检测。 目的3：探讨BLOD？2M水平对免疫系统的影响。 A.检测血液中2M水平对小鼠肿瘤后诱导T细胞反应能力的影响 接种； B.检测血液中2M水平对小鼠激发T细胞反应能力的影响 热休克蛋白-多肽复合体免疫。

ABSTRACT Heat shock proteins (HSPs) of the hsp70, hsp90 and calreticulin families are abundant soluble intracellular proteins that elicit powerful immunological responses. These responses include components of both the innate and adaptive aspects of T cell responses as well as its down regulation. The ability of HSPs to chaperone peptides and engage internalizing receptors on antigen presenting cells are two key properties that allow them to elicit immune responses. A key role for HSPs in cross- priming of antigens during T cell responses was also envisaged and demonstrated in 2005. In this application we aim to (i) investigate the role of the HSP receptor, CD91, in cross-priming in the murine system, (ii) examine the mechanism of immunogenicity of alpha2-macroglobulin (¿2M), a CD91 ligand, complexed either endogenously and artificially to various peptides, and (iii) test the role of serum levels of ¿2M on the ability of mice to mount immune responses. Aim 1: To investigate the role of the HSP receptor CD91 in cross-priming of T cell responses. a. Determine the ability of RAP (a competitive inhibitor of CD91) -expressing cells to cross present antigens and mount effective T cell responses; b. Creation of a CD91 conditional knock-out mouse and the characterization of immunological responses in this mouse. Aim 2: To investigate the mechanism of ¿2M-mediated immunogenicity and its application to immunotherapy of cancer and infectious disease. a. Examine the mechanism of co-stimulatory activation by ¿2M; b. Examination of the intracellular trafficking and processing of ¿2M-peptide complexes. c. Test the complexes of tumor derived-peptides with ¿2M in prophylaxis and therapy of cancers; d. Examination of endogenously formed ¿2M-peptide complexes as immunogens. Aim 3: To investigate the role of blodd ¿2M levels on immune system. a. Test the effects of blood ¿2M levels on the ability of mice to elicit T cell responses after tumor inoculation; b. Test the effects of blood ¿2M levels on the ability of mice to elicit T cell responses after immunization with HSP-peptide complexes.