CEA-Université Paris Sud 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, IBJF, DRF, Fontenay-aux-Roses, France.
Baylor Institute for Immunology Research, Dallas, TX, USA.
Cell Mol Life Sci. 2018 May;75(10):1871-1887. doi: 10.1007/s00018-017-2712-9. Epub 2017 Nov 13.
Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.
经典树突状细胞（cDC）在决定免疫反应是持续存在还是控制病毒方面起着关键作用。体外研究表明，HIV 感染通过 LILRB2 抑制性受体与其 MHC-I 配体结合，导致 cDC 失调，并且这种相互作用的强度被认为是驱动疾病进展的因素。然而，HIV 感染早期 cDC 中 LILRB2/MHC-I 抑制轴的动态变化尚不清楚。在这里，我们发现早期 HIV-1 感染会强烈且同时增加血液 cDC 表面的 LILRB2 和 MHC-I 的表达。我们进一步通过显示 SIVmac251 感染猕猴可促进 cDC 和单核细胞/巨噬细胞上 LILRB2 和 MHC-I 的协调上调，来描述 LILRB2 和 MHC-I 表达的早期动力学。对 LILRB2/MHC-I 抑制轴的定向始于感染的最初几天，并在急性期短暂诱导整个 cDC 群体。对涉及的因素的分析表明，HIV-1 复制、TLR7/8 触发以及 IL-10 或 I 型 IFNs 的治疗会增加 LILRB2 的表达。最后，LILRB2/MHC-I 抑制轴的增强是 HIV-1 和 SIVmac251 感染所特有的，因为猕猴自然控制的基孔肯雅病毒感染会降低 cDC 上 LILRB2 的表达。总之，我们的数据揭示了 SIV/HIV 感染早期 cDC 上 LILRB2 及其 MHC-I 配体的独特上调，这可能解释了抗病毒反应的关键阶段免疫失调的原因。
