The role of the RIG-I like receptors in mediating CD8+ T cell immunity during virus infection

Abstract

Abstract West Nile virus (WNV) is a mosquito-borne Flavivirus that is a major cause of virus-induced encephalitis in the US. Upon virus infection, pattern recognition receptors (PRRs) recognize viral PAMPs to trigger potent antiviral defense programs. In particular, the RIG-I-like receptors (RLRs) are a family of cytosolic PRRs that comprise of RIG-I, MDA5 and LGP2 and are expressed in nearly every host cell, including antigen-presenting cells. We have previously demonstrated that RLRs as well as their central adaptor protein mitochondria antiviral signaling (MAVS) are critical for mediating immune protection against WNV infection. Recently, we discovered that the RLRs function in a non-canonical manner within CD8+ T cells to promote T cell expansion, survival and effector function during virus infection. Specifically, we found that the RLR LGP2 plays an essential role in promoting virus-specific CD8+ T cell survival and effector functions. To better understand this novel RLR pathway in T cells, we evaluated the cell-intrinsic roles of RIG-I and MAVS, two known interacting partners of LGP2. Following in vitro CD8+T cell stimulation, we found that RIG-I−/−, but not MAVS−/−, CD8+ T cells displayed higher proliferation rates than wild type (WT) cells. Adoptive transfer studies into RAG−/− mice revealed that WNV-specific CD8+ T cells from RIG-I−/− or MAVS−/− mice were present in lower percentages than WT CD8+ T cells during virus infection. To define the non-canonical RLR signaling, we are undertaking a genetics approach to screen proteins associated with the RLR interactome in CD8+ T cells. Altogether, our data indicate that RLRs function in a noncanonical manner within CD8+ T cells to regulate antigen-specific responses during virus infection.