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: 9269291
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269291
• 关键词: Alloantigen; Anemia; 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; Immunologic Deficiency Syndromes; Knockout Mice; Lead; 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; Pathogenesis; Peptide Hydrolases; Peptides; Peripheral; Plasmodium; Play; Process; Proteins; Reporting; Research; Role; Solid; Staging; T cell response; T-Lymphocyte; TAP1 gene; TAP2 gene; Testing; Therapeutic; Time; Transplantation; Vaccine Design; Viral; Viral Antigens; Work; antigen processing; bacterial H antigen; dimer; graft vs host disease; improved; insight; leukemia/lymphoma; male; microbial; microorganism antigen; multicatalytic endopeptidase complex; novel; pathogen; response; tumor

Minor histocompatibility (H) antigens (Ags) play a detrimental role in the immuno-pathogenesis 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+ (TH) cells. Our mechanistic studies into indirect 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.

次要组织相容性 (H) 抗原 (Ag) 在移植物抗宿主的免疫发病机制中发挥有害作用 即使在 HLA 相同骨髓移植的受者中，也可能发生 GvHD 疾病（GvHD）。在此，受体次要 H Ag 是 由供体 Ag 呈递细胞 (APC) 获得，并由 MHC I 类分子处理和呈递 在一个被充分研究的过程中，称为交叉呈递，或者在一个不太了解的过程中通过 II 类分子 称为间接呈现。在实体器官移植环境中，间接呈现需要获取， 受者 APC 处理和呈递供者同种异体抗原。对于肿瘤和微生物 Ags，一种 II+ APC——相当于受体细胞——获得位于 II 类阴性细胞中的 Ag——相当于 供体细胞，对其进行处理并将其呈递给同源 CD4+ (TH) 细胞。我们对间接的机制研究 演示显示，雄性 pHY 和单核细胞增生李斯特氏菌衍生的 pLLO Ags 在获得后 受体 APC 能够接触细胞质。在此，pHY的间接表示为 免疫蛋白酶体依赖性 TAP（细胞质至 ER 肽转运蛋白）和 ERAAP（ER 相关 氨基肽酶）独立的。令人惊讶的是，TAP 和 ERAAP 都转移或破坏了 pHY 和 pLLO 从而减少它们向 TH 细胞的呈递。这些发现引出了两个关键问题：(a) I 类是否 银加工 (CAP) 机械在全球范围内影响 II 类限制银的呈现； (b) 细胞质如何 Ags 能够进入内切酶体/溶酶体进行间接呈递吗？在试图了解细胞质如何 pHY 返回到内切/溶酶体进行呈现，我们排除了宏观自噬作为间接的作用 HY 的呈递在树突状细胞条件性缺乏 Atg5 的小鼠中进行。相反，我们 发现同源二聚体 TAP 样 (TAP-L) - 一种与 ER 不同的孤儿内切/溶酶体肽转运蛋白 - 间接 pHY 表达需要驻留 TAP1/TAP2。根据我们的功能研究，本文中， 我们寻求获得对间接表达机制的生化见解。因此，我们将测试中央 假设 I 类 Ag 加工机制调节某些胞质 Ag 库，可用于 II 类——限制性间接表达。此类Ag在细胞质中被加工并转运至内/核 TAP-L 依赖性机制中的溶酶体。为了检验这个假设，我们将 (a) 确定 CAP 是否 机器在全球范围内影响 H2Ab 限制的自身或微生物来源的细胞质的加工和呈现 银； (b) 确定胞质 Ag 如何进入内质/溶酶体进行间接呈递； (c) 确定 CAP 机制是否影响胞质 Ag 特异性 CD4+ T 细胞库。顺利完成本次 这项工作将对 II 类分子的间接 Ag 呈递产生新的生化见解。机械论 了解 II 类限制性间接 Ag 表达不仅对于开发 规避/治疗 GvHD，也可用于疫苗设计，因为该过程在细胞溶质的呈现中起作用 TH 细胞的 Ag（病毒、细菌、寄生虫），因此可用于针对肿瘤和病原体的疫苗设计。