RIG-I-like Receptor Regulation of Immune Cell Function and Therapeutic Implications

Abstract

Retinoic acid-inducible gene I-like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.

Figure 1.. RLR domains, polymorphisms, and signaling.

A) The RLRs RIG-I, MDA5, and LGP2 all contain a C-terminal repressor domain (CTD) and a helicase domain. RIG-I and MDA5 contain two caspase activation and recruitment domains (CARDs). The numbered dashes represent relative locations of single nucleotide polymorphisms (SNPs) present in coding regions of the RLRs with numbers corresponding to Table I. B) Upon virus infection, RIG-I and MDA5 sense cognate RNAs and undergo confirmational change to allow for interaction with and activation of MAVS at mitochondrial-associated membranes (MAM) for downstream activation of NF-kB and IRF3 leading to antiviral gene programming, IFN production, immune cell programming genes, and pro-apoptotic genes. The role of LGP2 is still under investigation, but during acute infection it stabilizes and propagates MDA5 signaling. However, during resolution of infection LGP2 dampens RLR signaling.

Figure 2.. RLR functions in immune cell subsets.

The roles of RIG-I, MDA5 and LGP2 in dendritic cells, macrophages, natural killer cells, B lymphocytes, T lymphocytes, and granulocytes during infection are summarized. References for each function are color-coded: RIG-I (orange), MDA5 (teal), LGP2 (magenta).