Role of CD91 and its ligands in immune response

描述（由申请人提供）：hsp70、hsp90和钙网蛋白家族的热休克蛋白（HSPs）是丰富的可溶性细胞内蛋白，可引起强大的免疫反应。这些反应包括先天和适应性方面的T细胞反应及其下调的组成部分。热休克蛋白的伴侣肽和参与抗原呈递细胞的内化受体的能力是使它们引发免疫反应的两个关键特性。热休克蛋白在T细胞反应期间抗原交叉引物中的关键作用也在2005年被设想和证明。在这个应用程序中，我们的目标是(i)研究HSP受体CD91在小鼠系统交叉启动中的作用，（ii）检查CD91配体α 2-巨球蛋白（a2M）的免疫原性机制，该配体内源性和人工与各种肽络合，以及（iii）测试血清a2M水平对小鼠免疫反应能力的作用。目的1：探讨热休克蛋白受体CD91在T细胞交叉启动反应中的作用。a.确定RAP（一种CD91的竞争性抑制剂）表达细胞的能力，使其能够交叉现呈抗原并产生有效的T细胞反应；b. CD91条件敲除小鼠的创建和该小鼠免疫反应的表征。目的2：探讨a2m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.检验a2M共刺激激活的机制；b. a2M -肽复合物的细胞内运输和加工的检查。c.检测肿瘤源肽与a2M复合物在预防和治疗癌症中的作用；d.检查内源性形成的a2M -肽复合物作为免疫原。目的3：探讨血液中a2M水平对免疫系统的影响。a.检测肿瘤接种后血液a2M水平对小鼠诱导T细胞应答能力的影响；b.检测血a2M水平对热休克蛋白肽复合物免疫后小鼠诱导T细胞应答能力的影响。

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.