Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
PLoS Pathog. 2019 Jul 22;15(7):e1007918. doi: 10.1371/journal.ppat.1007918. eCollection 2019 Jul.
T-follicular helper (Tfh) cells, co-expressing PD-1 and TIGIT, serve as a major cell reservoir for HIV-1 and are responsible for active and persistent HIV-1 transcription after prolonged antiretroviral therapy (ART). However, the precise mechanisms regulating HIV-1 transcription in lymph nodes (LNs) remain unclear. In the present study, we investigated the potential role of immune checkpoint (IC)/IC-Ligand (IC-L) interactions on HIV-1 transcription in LN-microenvironment. We show that PD-L1 (PD-1-ligand) and CD155 (TIGIT-ligand) are predominantly co-expressed on LN migratory (CD1chighCCR7+CD127+) dendritic cells (DCs), that locate predominantly in extra-follicular areas in ART treated individuals. We demonstrate that TCR-mediated HIV production is suppressed in vitro in the presence of recombinant PD-L1 or CD155 and, more importantly, when LN migratory DCs are co-cultured with PD-1+/Tfh cells. These results indicate that LN migratory DCs expressing IC-Ls may more efficiently restrict HIV-1 transcription in the extra-follicular areas and explain the persistence of HIV transcription in PD-1+/Tfh cells after prolonged ART within germinal centers.
滤泡辅助性 T 细胞（Tfh）细胞共表达 PD-1 和 TIGIT，是 HIV-1 的主要细胞储存库，负责在长期抗逆转录病毒治疗（ART）后持续活跃和持续的 HIV-1 转录。然而，调节淋巴结（LN）中 HIV-1 转录的确切机制仍不清楚。在本研究中，我们研究了免疫检查点（IC）/IC-配体（IC-L）相互作用在 LN 微环境中对 HIV-1 转录的潜在作用。我们表明，PD-L1（PD-1 配体）和 CD155（TIGIT 配体）主要在 LN 迁移（CD1chighCCR7+CD127+）树突状细胞（DC）上共表达，这些细胞主要位于 ART 治疗个体的滤泡外区域。我们证明，在存在重组 PD-L1 或 CD155 的情况下，TCR 介导的 HIV 产生在体外受到抑制，更重要的是，当 LN 迁移性 DC 与 PD-1+/Tfh 细胞共培养时。这些结果表明，表达 IC-L 的 LN 迁移性 DC 可能更有效地限制滤泡外区域的 HIV-1 转录，并解释了 PD-1+/Tfh 细胞在生发中心内长期接受 ART 后 HIV 转录的持续存在。
