Research Article: RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection

Date Published: July 20, 2016

Publisher: Public Library of Science

Author(s): Matheswaran Kandasamy, Amol Suryawanshi, Smanla Tundup, Jasmine T. Perez, Mirco Schmolke, Santhakumar Manicassamy, Balaji Manicassamy, Kanta Subbarao.

http://doi.org/10.1371/journal.ppat.1005754

Abstract

Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 –MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains.

Partial Text

Influenza A virus (IAV), a member of the Orthomyxoviridae family, has a genome composed of eight single-stranded negative sense RNAs, each containing a 5’ triphosphate end (5’-ppp)[1]. IAV infection of a cell is detected by the intracellular innate immune sensor retinoic acid inducible gene-I (RIG-I), which recognizes and binds to the 5’-ppp with double stranded RNA structure found within the panhandle of the IAV genome[2,3]. Upon binding of viral RNA, RIG-I is activated and interacts with the adaptor protein mitochondrial antiviral signaling (MAVS) [also known as interferon-β promoter stimulator-1 (IPS-1) and virus induced signaling adaptor (cardif/VISA)] to elicit antiviral and pro-inflammatory responses through interferon regulatory factor 3 (IRF-3) and nuclear factor κB (NF-κB, respectively[4].

In this study, we demonstrate that RIG-I signaling via MAVS is critical for both innate and adaptive immune responses, as we observe increased IAV infection in various cellular compartments, reduced polyfunctional T cell responses, and delayed viral clearance in RIG-I-/- mice. We show that loss of RIG-I signaling leads to inefficient activation of CD103+ migratory DC and subsequent suboptimal priming of naïve T cells, resulting in decreased frequencies of polyfunctional T cells (Figs 4 and 6). As such, the suboptimal activation of T cells results in delayed clearance of virus and decreased protection against subsequent IAV infection from a heterologous IAV strain. (Figs 1 and 5). Exogenous addition of type I IFN to BMDC-T cell co-cultures increased expression of CD86/MHC-II in RIG-I-/- BMDC and partly restored the levels of IFNγ producing CD8+ T cells (S10 Fig). Moreover, treatment of PR8 infected RIG-I-/- mice with poly I:C at 24hpi improved polyfunctional T cell responses against IAV (Fig 7). Unlike the RIG-I-MAVS pathway, TLR7 is critical for efficient CD4+ T cell responses but dispensable for CD8+ T cell responses against IAV (Fig 8). Taken together, these results indicate that the deficiency of RIG-I and MAVS results in insufficient activation of antigen presenting cells, which functions to (1) restrict viral replication in different cellular compartments, and (2) modulate DC activation and polyfunctional T cell responses. Importantly, our study demonstrates that while the RIG-I-MAVS pathway may be sufficient for efficient CD8+ T cell responses against IAV, both the RIG-I and TLR7 pathways are required for efficient CD4+ T cell responses against IAV.

 

Source:

http://doi.org/10.1371/journal.ppat.1005754

 

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