Nucleic acid sensing in CD8 T cells and NK cells during viral infections

Abstract

Pathogens can be detected by a variety of germline encoded pattern recognition receptors (PRR) that recognize highly conserved pathogen-associated molecular patterns (PAMPs). Among these receptors, Retinoic Acid-Inducible Gene I (RIG-I), a type I IFN (IFN-I) inducing sensor of cytosolic pathogen-derived RNA, plays a key role in the immune responses to RNA viruses in macrophages and dendritic cells. However, the specific impact of RIG-I activation on lymphocyte function has remained poorly understood. This in vitro study aimed to investigate the role of RIG-I in human NK and CD8 T cells. Activation of RIG-I by influenza A virus infection or the synthetic RIG-I ligand 3p-dsRNA demonstrated that both stimuli resulted in the production of IFN-I, which not only activated these cytotoxic lymphocytes but also significantly enhanced their degranulation and cytokine production. Pre-stimulation by 3p-dsRNA also significantly reduced the ability of influenza A virus to infect these cells. To further investigate the role of RIG-I receptors and the secreted IFN-I stimulated by influenza A infection and 3p-dsRNA, we employed CRISPR/Cas9-mediated gene editing in primary human lymphocytes. This approach demonstrated the involvement of RIG-I and STAT2 in the signalling pathway leading to the activation of cytotoxic lymphocytes. Altogether, the data shows that RIG-I activation not only protects lymphocytes from infection by inducing cell autonomous antiviral pathways in the lymphocytes themselves but also enhances lymphocyte effector function. This research contributes to our understanding of lymphocyte responses to viral infections, emphasizing the importance of RIG-I as a nucleic acid sensor in lymphocyte effector function and raise the possibility of activating RIG-I to enhance their effector function in cellular therapies.