Role of CD91 and its ligands in immune response

摘要 热休克蛋白（heat shock proteins，HSP 70，HSP 90）和钙网蛋白（calreticulin）家族的热休克蛋白（heat shock proteins，HSPs）是一种可溶性蛋白， 细胞内的蛋白质，引发强大的免疫反应。这些反应包括 T细胞应答的先天和适应性方面的组分以及其下调。 热休克蛋白分子伴侣肽和参与抗原呈递的内化受体的能力 细胞是两个关键的属性，使他们能够引发免疫反应。HSPs在跨- 2005年还设想并证明了在T细胞应答期间抗原的引发。 在本申请中，我们的目的是（i）研究HSP受体CD 91在交叉启动中的作用， 小鼠系统，（ii）检查α 2-巨球蛋白（<$2M），一种CD 91 配体，内源性和人工复合到各种肽，和（iii）测试的作用， 血清中的~ 2 M水平对小鼠产生免疫反应的能力的影响。 目的1：探讨热休克蛋白受体CD 91在T细胞交叉致敏反应中的作用。 a.确定RAP（CD 91的竞争性抑制剂）表达细胞交叉呈递的能力 抗原并产生有效的T细胞应答; B. CD 91条件性基因敲除小鼠的建立及其免疫学特性的表征 这只老鼠的反应。 目的2：探讨~ 2 M介导免疫原性的机制及其在免疫治疗中的应用。 癌症和传染病免疫治疗。 a.探讨~ 2 M激活共刺激分子的机制; B.检查2 M-肽复合物的细胞内运输和加工。 C.检测肿瘤衍生肽与~ 2 M的复合物在癌症预防和治疗中的作用; D.检查内源性形成的2 M-肽复合物作为免疫原。 目的3：探讨血卟啉-2-M水平在免疫系统中的作用。 a.测试血液中<$2M水平对小鼠在肿瘤后引发T细胞应答的能力的影响。 接种; B.测试血液中2 M水平对小鼠在免疫后引发T细胞应答的能力的影响。 用HSP-肽复合物免疫。

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.