Processing and Presentation of Minor Histocompatibility Antigens that Cause GvHD

引起 GvHD 的次要组织相容性抗原的加工和呈递

• 批准号: 9250188
• 负责人: SEBASTIAN JOYCE
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250188
• 关键词: Alloantigen; Anemia; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autophagocytosis; Back; Biochemical; Blood Cells; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cross Presentation; Cytoplasm; Cytosol; Dendritic Cells; Disease; Goals; Histocompatibility; Histocompatibility Antigens Class I; Impairment; Knockout Mice; Listeria; Listeria monocytogenes; Lysosomes; MHC Class II Genes; Major Histocompatibility Complex; Mediating; Microbe; Minor; Minor Histocompatibility Antigens; Modality; Molecular Chaperones; Mus; Organ Transplantation; Orphan; Outcome; Peptide Hydrolases; Peptides; Peripheral; Plasmodium; Play; Process; Reporting; Research; Role; Solid; T-Lymphocyte; TAP1 gene; TAP2 gene; Testing; Therapeutic; Time; Transplantation; Tumor Antigens; Vaccine Design; Viral; Work; antigen processing; graft vs host disease; improved; insight; leukemia/lymphoma; male; microbial; microorganism antigen; multicatalytic endopeptidase complex; novel; pathogen; public health relevance; response; tumor

DESCRIPTION (provided by applicant): Minor histocompatibility (H) antigens (Ags) play a detrimental role in the immunopathogenesis of graft-vs-host disease (GvHD) even in recipients of HLA identical bone marrow transplants. Herein, recipient minor H Ags are acquired by donor Ag-presenting cells (APCs) and processed and presented either by MHC class I molecules in a well-studied process termed cross-presentation or by class II molecules in a less well understood process called indirect presentation. In a solid organ transplant setting, indirect presentation entails the acquisition, processing and presentation of donor alloantigens by the recipient's APCs. In the case of tumour and microbial Ags, a class II+ APC-likened to a recipient cell-acquires the Ag residing in a class II-negative cell-likened to a donor cell-and processes and presents it to cognate CD4+ (T) cells. Our mechanistic studies into indirect H presentation revealed that the male pHY and Listeria monocytogenes-derived pLLO Ags upon acquisition by the recipient APCs gained access to the cytosol. Herein, the indirect presentation of pHY was immunoproteasome-dependent yet TAP (cytosol to ER peptide transporter)- and ERAAP (ER-associated amino-peptidase)-independent. Surprisingly, both TAP and ERAAP either diverted or destroyed pHY and pLLO thereby reducing their presentation to TH cells. These finding led to two critical questions: (a) does the class I Ag processing (CAP) machinery globally impact class II-restricted Ag presentation; and (b) how do cytosolic Ags gain access to the endo/lysosomes for indirect presentation? In trying to understand how the cytosolic pHY returned to the endo/lysosomes for presentation, we ruled out the role for macro-autophagy as indirect presentation of HY proceeded in mice in which dendritic cells were conditionally deficient for Atg5. Instead, we found that the homodimeric TAP-like (TAP-L)-an orphan endo/lysosomal peptide transporter distinct from ER-resident TAP1/TAP2-was needed for indirect pHY presentation. Predicated on our functional studies, herein, we seek to gain biochemical insights into indirect presentation mechanism(s). Hence, we will test the central hypothesis that the class I Ag processing machinery regulates the pool of certain cytosolic Ags available for class II-restricted indirect presentation. Such Ags are processed in the cytosol and transported to the endo/ lysosomes in a TAP-L-dependent mechanism. To test this hypothesis, we will (a) determine whether the CAP machinery globally impacts H2Ab-restricted processing and presentation of self- or microbe-derived cytosolic Ags; (b) determine how cytosolic Ags enter the endo/lysosomes for indirect presentation; and (c) determine whether the CAP machinery impacts cytosolic Ag specific CD4+ T cell repertoire. Successful completion of this work will yield new biochemical insight(s) into indirect Ag presentation by class II molecules. A mechanistic understanding of class II-restricted indirect Ag presentation is critical not only for developing ways to circumvent/treat GvHD but also for vaccine design as this process is operative in the presentation of cytosolic Ags (viral, bacterial, parasitic) to TH cells and, hence for vaccine design against tumours and pathogens.

描述（由申请人提供）：次要组织相容性（H）抗原（Ag）在移植物抗宿主病（GvHD）的免疫发病机制中起有害作用，即使在HLA相同的骨髓移植受者中也是如此。在本文中，受体次要HAg由供体Ag呈递细胞（APC）获得，并在称为交叉呈递的充分研究的过程中由MHC I类分子或在称为间接呈递的不太了解的过程中由II类分子加工和呈递。在实体器官移植环境中，间接呈递需要受体的APC对供体同种异体抗原的获取、加工和呈递。在肿瘤和微生物Ag的情况下，II类+APC-类似于受体细胞-获得存在于II类阴性细胞-类似于供体细胞-中的Ag，并将其加工并呈递给同源CD 4+（T）细胞。我们对间接H呈递的机制研究表明，雄性pHY和单核细胞增生李斯特菌衍生的pLLO Ag在被受体APC获得后进入胞质溶胶。在本文中，pHY的间接呈递是免疫蛋白酶体依赖性的，但TAP（细胞质到ER肽转运蛋白）和ERAAP（ER相关氨基肽酶）不依赖。令人惊讶的是，TAP和ERAAP都转移或破坏pHY和pLLO，从而减少它们对TH细胞的呈递。这些发现导致了两个关键问题：（a）I类Ag加工（CAP）机制是否全面影响II类限制性Ag呈递;以及（B）胞质Ag如何进入内/溶酶体进行间接呈递？在试图理解胞质pHY如何返回到内/溶酶体中进行呈递时，我们排除了巨自噬的作用，因为HY的间接呈递在其中树突状细胞有条件地缺乏Atg 5的小鼠中进行。相反，我们发现，同源二聚体TAP样（TAP-L）-一个孤儿endo/溶酶体肽转运蛋白不同于ER居民TAP 1/TAP 2-需要间接pHY介绍。基于我们的功能研究，本文中，我们寻求获得间接呈递机制的生化见解。因此，我们将测试中心的假设，即I类抗原加工机制调节池的某些胞质抗原可用于II类限制性间接介绍。这样的Ag在胞质溶胶中加工并以TAP-L依赖性机制转运至内体/溶酶体。为了检验这一假设，我们将（a）确定CAP机制是否全面影响H2 Ab限制的自身或微生物来源的胞质Ag的加工和呈递;（B）确定胞质Ag如何进入内体/溶酶体进行间接呈递;和（c）确定CAP机制是否影响胞质Ag特异性CD 4 + T细胞库。这项工作的成功完成将产生新的生物化学见解间接银介绍II类分子。对II类限制性间接Ag呈递的机制理解不仅对于开发规避/治疗GvHD的方法而且对于疫苗设计是至关重要的，因为该过程在胞质Ag（病毒、细菌、寄生虫）向TH细胞的呈递中是有效的，因此对于针对肿瘤和病原体的疫苗设计是至关重要的。