Toll 样受体激动剂增强浆细胞样树突状细胞介导的不同 HIV-1 疾病进展表型中 HIV 特异性 T 细胞反应。
Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypes.
机构信息
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain.
Immunology Section, Laboratorio InmunoBiología Molecular (LIBM), Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Area of Immune System Pathology, Madrid, Spain.
出版信息
EBioMedicine. 2023 May;91:104549. doi: 10.1016/j.ebiom.2023.104549. Epub 2023 Apr 3.
BACKGROUND
Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors.
METHODS
pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed.
FINDINGS
pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC.
INTERPRETATION
These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies.
FUNDING
This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, "a way to make Europe") and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).
背景
浆细胞样树突状细胞（pDCs）通过 Toll 样受体（TLR）-7 和 -9 感知病毒和细菌产物，并将这种感应转化为干扰素-α（IFN-α）的产生和 T 细胞的激活。了解 pDCs 刺激的机制可能有助于 HIV 治愈的免疫治疗策略。本研究的目的是描述 TLR 激动剂刺激在几种 HIV-1 疾病进展表型和非 HIV-1 感染供体中的免疫调节作用。
方法
从非 HIV-1 感染供体、免疫应答者（IR）、免疫无应答者（INR）、病毒血症（VIR）和精英控制者（EC）参与者的 450ml 全血中分离出 pDCs、CD4 和 CD8 T 细胞。pDCs 用 AT-2、CpG-A、CpG-C 和 GS-9620 或无刺激物过夜刺激。之后，将 pDCs 与自体 CD4 或 CD8 T 细胞共培养，并与/或不与 HIV-1（Gag 肽库）或 SEB（葡萄球菌肠毒素 B）共培养。测定细胞因子阵列、基因表达和深度免疫表型。
结果
在不同的 HIV 疾病进展表型中，TLR 刺激后，pDCs 显示出激活标志物水平、干扰素相关基因、HIV-1 限制因子和细胞因子水平的增加。这种 pDC 激活在 CpG-C 和 GS-9620 中更为明显，并诱导即使在 VIR 和 INR 中也可与 EC 相媲美的 HIV 特异性 T 细胞反应。这种 HIV-1 特异性 T 细胞反应与 pDC 中 HIV-1 限制因子和 IFN-α的上调有关。
结论
这些结果揭示了与 TLR 特异性 pDCs 刺激相关的机制，该机制与诱导 T 细胞介导的抗病毒反应有关，这对于 HIV-1 清除策略至关重要。
资助
这项工作得到了吉利德奖学金计划、西班牙卡洛斯三世健康研究所（欧洲区域发展基金，FEDER）和合作性艾滋病研究主题网络以及西班牙国家研究理事会（CSIC）的支持。
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