Borrelia burgdorferi-Induced Changes in the Class II Self-Immunopeptidome Displayed on HLA-DR Molecules Expressed by Dendritic Cells.
Borrelia burgdorferi-Induced Changes in the Class II Self-Immunopeptidome Displayed on HLA-DR Molecules Expressed by Dendritic Cells.
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DOI：
10.3389/fmed.2020.00568
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发表时间：
2020
影响因子：
3.9
通讯作者：
Soloski MJ
中科院分区：
文献类型：
--
作者：
Gutierrez-Hoffmann MG;O'Meally RN;Cole RN;Tiniakou E;Darrah E;Soloski MJ
MHC-II类抗原的处理和递呈途径已经进化为从进入内吞途径的蛋白质中提取短氨基酸肽，将它们装载到MHC-II类分子上，并将它们展示在抗原递呈细胞的表面，以供CD4+T细胞识别。在正常情况下，与MHC II类分子结合的多肽来自宿主(自身)蛋白，由于耐受机制而不被T细胞识别。病原体引起抗原提呈细胞生物学上的重大变化，包括MHC加工和提呈的上调。因此，我们假设接触病原体可能会改变与MHC II类分子结合的自体多肽的谱系。为了验证这一假设，我们从健康受试者中分离出单核细胞来源的树突状细胞，将它们暴露于TLR-2激动剂脂磷壁酸或莱姆病的病原体伯氏疏螺旋体，并利用质谱仪分离和鉴定了人类白细胞抗原-DR相关多肽。我们的结果表明，脂磷壁酸刺激、伯氏杆菌刺激和未刺激的单核细胞来源的树突状细胞主要从相似的重叠宿主蛋白集合中获得自体多肽。然而，脂磷壁酸和伯氏杆菌的刺激促进了来自独特蛋白质来源的新的与HLA-DR相关的自肽的处理和呈现。对这些蛋白质存在的过程和隔室的检查表明，单核细胞来源的树突状细胞的激活改变了可用于加工和呈递MHC II类分子的宿主自身蛋白质的范围。这些发现表明，由mo-DC呈递的与HLA-DR结合的自身免疫肽本质上是动态的，并且随着反映细胞功能的激活状态的变化而变化。此外，在与人类白细胞抗原-DR结合的自体肽中，有几个已知的表位可被自身反应性T细胞识别。这些研究与我们对病原体诱导的单核细胞来源的树突状细胞功能的变化以及感染诱导的自身免疫性疾病(如莱姆关节炎)所涉及的机制的基本理解有关。
The MHC class II antigen processing and presentation pathway has evolved to derive short amino acid peptides from proteins that enter the endocytic pathway, load them onto MHC class II molecules and display them on the surface of antigen presenting cells for recognition by CD4+ T cells. Under normal circumstances, peptides bound to MHC class II molecules are derived from host (self) proteins and not recognized by T cells due to tolerance mechanisms. Pathogens induce significant changes in the biology of antigen presenting cells, including upregulation of MHC processing and presentation. We therefore hypothesized that exposure to pathogens may alter the repertoire of self-peptides bound to MHC class II molecules. To test this hypothesis, we isolated monocyte-derived dendritic cells from healthy subjects, exposed them to the TLR-2 agonist lipoteichoic acid or live Borrelia burgdorferi, the causative agent of Lyme disease, and isolated and characterized HLA-DR associated peptides using mass spectrometry. Our results show that lipoteichoic acid-stimulated, B. burgdorferi-stimulated and unstimulated monocyte-derived dendritic cells largely derive their self-peptides from similar overlapping sets of host proteins. However, lipoteichoic acid and B. burgdorferi stimulation promote the processing and presentation of new sets of HLA-DR associated self-peptides derived from unique protein sources. Examination of processes and compartments these proteins reside in, indicate that activation of monocyte-derived dendritic cells changes the range of host self-proteins available for processing and presentation on MHC class II molecules. These findings reveal that the HLA-DR-bound self-immunopeptidome presented by mo-DCs is dynamic in nature and changes with activation state reflective of cellular function. In addition, among the repertoire of self-peptides bound to HLA-DR are several epitopes known to be recognized by autoreactive T cells. These studies are relevant to our basic understanding of pathogen-induced changes in monocyte-derived dendritic cell function, and the mechanisms involved in infection-induced autoimmune illnesses such as Lyme arthritis.
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影响因子：
8.8
作者：
Sivridis E;Giatromanolaki A;Papadopoulos I;Gatter KC;Harris AL;Koukourakis MI
通讯作者：
Koukourakis MI
影响因子：
5.1
作者：
Holoshitz J
通讯作者：
Holoshitz J
影响因子：
13.3
作者：
Bockenstedt, Linda K.;Wormser, Gary P.
通讯作者：
Wormser, Gary P.
影响因子：
3.7
作者：
Brandt KJ;Fickentscher C;Kruithof EK;de Moerloose P
通讯作者：
de Moerloose P
影响因子：
6.4
作者：
Jensen, Kamilla Kjaergaard;Andreatta, Massimo;Nielsen, Morten
通讯作者：
Nielsen, Morten