Role of CD91 and its ligands in immune response

描述（由申请人提供）：热休克蛋白70、热休克蛋白90和钙网蛋白家族的热休克蛋白（HSP）是丰富的可溶性细胞内蛋白，其引起强大的免疫应答。这些反应包括T细胞反应的先天性和适应性方面的组分以及其下调。热休克蛋白的能力，伴侣肽和参与内化受体的抗原呈递细胞是两个关键的性质，使他们能够引发免疫反应。2005年还设想并证明了热休克蛋白在T细胞应答期间抗原交叉致敏中的关键作用。在本申请中，我们的目的是（i）研究HSP受体CD 91在鼠系统中交叉致敏中的作用，（ii）检查α 2-巨球蛋白（α 2 M）（一种CD 91配体）的免疫原性机制，所述α 2-巨球蛋白（α 2 M）内源性地或人工地与各种肽复合，以及（iii）测试α 2 M的血清水平对小鼠产生免疫应答的能力的作用。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）表达细胞交叉呈递抗原和产生有效T细胞应答的能力; B. CD 91条件性敲除小鼠的产生和该小鼠中免疫应答的表征。目的2：探讨α 2 M介导的免疫原性机制及其在肿瘤和感染性疾病免疫治疗中的应用。a.检查a2 M的共刺激激活机制; B.α 2 M-肽复合物的细胞内运输和加工的检查。C.测试肿瘤衍生肽与a2 M的复合物在预防和治疗癌症中的作用; d.检查内源性形成的α 2 M-肽复合物作为免疫原。目的3：探讨血α 2 M水平对免疫系统的作用。a.测试血液α 2 M水平对小鼠在肿瘤接种后引发T细胞应答的能力的影响; B.测试血液α 2 M水平对小鼠在用HSP-肽复合物免疫后引发T细胞应答的能力的影响。 公共卫生相关性：我们已经确定了热休克蛋白在交叉启动中的作用，交叉启动是启动针对癌症和传染病的适应性免疫反应的核心事件。在这个建议中，我们的目标是检查HSP受体（S）参与和我们如何可以利用这个受体通过通道其他配体，如α 2-巨球蛋白通过这一途径。这将允许人们通过靶向细胞表面受体来产生针对癌症和传染病的新型治疗剂。

DESCRIPTION (provided by applicant): 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 (a2M), a CD91 ligand, complexed either endogenously and artificially to various peptides, and (iii) test the role of serum levels of a2M 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 a2M-mediated immunogenicity and its application to immunotherapy of cancer and infectious disease. a. Examine the mechanism of co-stimulatory activation by a2M; b. Examination of the intracellular trafficking and processing of a2M -peptide complexes. c. Test the complexes of tumor derived-peptides with a2M in prophylaxis and therapy of cancers; d. Examination of endogenously formed a2M -peptide complexes as immunogens. Aim 3: To investigate the role of blood a2M levels on immune system. a. Test the effects of blood a2M levels on the ability of mice to elicit T cell responses after tumor inoculation; b. Test the effects of blood a2M levels on the ability of mice to elicit T cell responses after immunization with HSP-peptide complexes. PUBLIC HEALTH RELEVANCE: We have identified a role for heat shock proteins in cross-priming, an event that is central to the initiation of adaptive immune responses against cancer and infectious disease. In this proposal we aim to examine the HSP receptor(s) involved and how we may exploit this receptor by channeling other ligands, such as a2-macroglobulin through this pathway. This will allow one to generate novel therapeutic agents against cancer and infectious disease by targeting cell surface receptors.