Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.
Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.
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DOI：
10.1371/journal.ppat.1004725
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Le Gall S
中科院分区：
文献类型：
--
作者：
Dinter J;Duong E;Lai NY;Berberich MJ;Kourjian G;Bracho-Sanchez E;Chu D;Su H;Zhang SC;Le Gall S
树突状细胞（DC）和巨噬细胞（Møs）内化并加工外源性HIV衍生抗原，以通过MHC-I交叉呈递给细胞毒性CD 8 + T细胞（CTL）。然而，HIV抗原在交叉呈递途径中的降解模式如何影响免疫优势和免疫逃逸尚不清楚。在这里，我们研究了单核细胞衍生的DCs和Møs对显性和亚显性HIV-1 Gag衍生表位和HLA限制性突变体的加工和交叉呈递。DC和Møs对HIV蛋白的交叉提呈导致对免疫优势表位具有更高特异性的CTL反应。通过用肽酶抑制剂预处理靶细胞，增加了对亚优势表位的低CTL应答，提示相应肽的细胞内降解更高。使用DC和Mesophageal细胞提取物作为细胞溶质、内体或溶酶体蛋白酶降解长HIV肽的来源，我们通过质谱鉴定了细胞特异性和隔室特异性降解模式，这有利于在所有隔室中产生含有免疫显性表位的肽。最佳的HIV-1表位的细胞内稳定性加载到MHC之前是高度可变的和序列依赖性的所有隔室，并遵循CTL层次与免疫显性表位呈现较高的稳定率。在急性HIV感染期间出现的显性表位中的常见HLA相关突变修改了长HIV肽的降解模式，降低了交叉呈递能力细胞隔室中的细胞内稳定性和表位产生，表明交叉呈递途径中的表位产生受损有助于免疫逃逸。这些发现突出了交叉呈递途径中的降解模式对HIV免疫优势的贡献，并首次证明了免疫逃逸影响表位交叉呈递。病原体如HIV可以通过在质膜融合以在细胞溶质中递送或通过在内溶酶体囊泡中内化而进入细胞。病原体可以在这些不同的区室中降解成通过MHC-I展示在细胞表面的肽（表位）。病原体衍生肽的呈递触发T细胞免疫应答的激活和感染细胞的清除。HIV运输区室的多样性与HIV序列的多样性如何影响HIV的降解和免疫细胞对感染细胞的识别尚不清楚。我们比较了树突状细胞和巨噬细胞的亚细胞区室中HIV蛋白的降解，这两种细胞类型被HIV靶向，并随后将表位呈递给T细胞。我们显示可变的降解模式的HIV根据车厢，和优先生产和上级细胞内稳定性的免疫优势表位对应于更强的T细胞反应。在急性感染期间，免疫显性表位的频繁突变导致这些表位的产生和细胞内稳定性降低。这些结果共同证明了蛋白质降解模式在形成免疫显性表位中的重要性，以及在HIV感染期间所有细胞隔室中受损表位产生对免疫逃逸的贡献。
Dendritic cells (DCs) and macrophages (Møs) internalize and process exogenous HIV-derived antigens for cross-presentation by MHC-I to cytotoxic CD8+ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Møs. The cross-presentation of HIV proteins by both DCs and Møs led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mø cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross-presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross-presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation. Pathogens such as HIV can enter cells by fusion at the plasma membrane for delivery in the cytosol, or by internalization in endolysosomal vesicles. Pathogens can be degraded in these various compartments into peptides (epitopes) displayed at the cell surface by MHC-I. The presentation of pathogen-derived peptides triggers the activation of T cell immune responses and the clearance of infected cells. How the diversity of compartments in which HIV traffics combined with the diversity of HIV sequences affects the degradation of HIV and the recognition of infected cells by immune cells is not understood. We compared the degradation of HIV proteins in subcellular compartments of dendritic cells and macrophages, two cell types targeted by HIV and the subsequent presentation of epitopes to T cells. We show variable degradation patterns of HIV according to compartments, and the preferential production and superior intracellular stability of immunodominant epitopes corresponding to stronger T cell responses. Frequent mutations in immunodominant epitopes during acute infection resulted in decreased production and intracellular stability of these epitopes. Together these results demonstrate the importance of protein degradation patterns in shaping immunodominant epitopes and the contribution of impaired epitope production in all cellular compartments to immune escape during HIV infection.
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