Credit: Macmillan Australia

The cytosolic RNA helicases of the RIG-I-like receptor (RLR) family are pattern-recognition receptors that recognize viral RNA. The roles of two RLRs (namely, RIG-I and MDA5) in the induction of innate antiviral immunity have been well described, but the function of the third family member, LGP2 (encoded by Dhx58), is not fully known. Reporting in Immunity, Suthar et al. describe a cell-intrinsic role for LGP2 in promoting the survival and effector functions of CD8+ T cells in response to RNA viruses.

LGP2 is required for the survival of virus-specific CD8+ T cells

To examine the antiviral immune function of LGP2, the authors generated Dhx58−/− mice, for the first time on a pure C57BL/6 background. Dhx58−/− dendritic cells and macrophages that were infected in vitro with West Nile virus (WNV) showed similar control of virus replication to infected wild-type cells, but the level of interferon-β (IFNβ) produced by the Dhx58−/− innate cells was lower. These in vitro results suggest that LGP2 has a non-essential but positive regulatory role in innate antiviral immune responses.

However, infection of Dhx58−/− mice with WNV resulted in increased mortality compared with controls. No differences in tissue viral load, innate immune responses or viral neuroinvasion were observed between Dhx58−/− and wild-type mice. However, higher viral loads were observed in the brains of Dhx58−/− mice at later time points during infection. Furthermore, infected Dhx58−/− mice had greatly reduced numbers of CD8+ T cells in the brain compared with controls.

Given that CD8+ T cells are known to have an important role in controlling WNV-induced pathology in the central nervous system, the authors next assessed the role of LGP2 in regulating CD8+ T cells. They found that LGP2 is required for the survival of virus-specific CD8+ T cells. Furthermore, the frequency and number of virus-specific CD8+ T cells producing effector cytokines at later time points were reduced in infected Dhx58−/− mice compared with infected wild-type mice. Similar results were observed following infection with the RNA virus lymphocytic choriomeningitis virus.

But is the role of LGP2 in CD8+ T cell survival and function cell intrinsic or extrinsic? T cell receptor- and IFNβ-mediated signalling in CD8+ T cells was shown to induce LGP2 expression. Furthermore, following the transfer of equal numbers of Dhx58−/− and wild-type CD8+ T cells to lymphocyte-deficient mice and subsequent infection, only virus-specific Dhx58−/− CD8+ T cells showed defects in survival and effector function, indicating that LGP2 functions in a T cell-intrinsic manner. Finally, LGP2 was shown to regulate CD8+ T cell survival by regulating the sensitivity of these cells to CD95 ligand-mediated cell death during virus infection through the control of CD95 expression.

So, LGP2 promotes antiviral immunity through the cell-intrinsic regulation of CD8+ T cell survival and effector function.