Inhibition of iNKT Cells by the HLA-G-ILT2 Checkpoint and Poor Stimulation by HLA-G-Expressing Tolerogenic DC

• Published in: Frontiers in immunology 2021-01, Vol.11, p.608614-608614
• Main Authors: Wu, Ching-Lien, Caumartin, Julien, Amodio, Giada, Anna, François, Loustau, Maria, Gregori, Silvia, Langlade-Demoyen, Pierre, LeMaoult, Joel
• Format: Article
• Language: English
• Subjects: Human Leucocyte Antigen G; ILT2/CD85j/LILRB1; immune regulation; Immunology; Natural Killer T cells; tolerogenic dendritic cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.608614

Invariant Natural Killer T (iNKT) cells are a small and distinct population of T cells crucial in immunomodulation. After activation by alpha-GalactosylCeramide (αGC), an exogenic glycolipid antigen, iNKT cells can rapidly release cytokines to enhance specific anti-tumor activity. Several human clinical trials on iNKT cell-based anti-cancer are ongoing, however results are not as striking as in murine models. Given that iNKT-based immunotherapies are dependent mainly on antigen-presenting cells (APC), a human tolerogenic molecule with no murine homolog, such as Human Leucocyte Antigen G (HLA-G), could contribute to this discrepancy. HLA-G is a well-known immune checkpoint molecule involved in fetal-maternal tolerance and in tumor immune escape. HLA-G exerts its immunomodulatory functions through the interaction with immune inhibitory receptors such as ILT2, differentially expressed on immune cell subsets. We hypothesized that HLA-G might inhibit iNKT function directly or by inducing tolerogenic APC leading to iNKT cell anergy, which could impact the results of current clinical trials. Using an ILT2-transduced murine iNKT cell line and human iNKT cells, we demonstrate that iNKT cells are sensitive to HLA-G, which inhibits their cytokine secretion. Furthermore, human HLA-G dendritic cells, called DC-10, failed at inducing iNKT cell activation compared to their autologous HLA-G DCs counterparts. Our data show for the first time that the HLA-G/ILT2 ICP is involved in iNKT cell function modulation.