Activation of RIG-I pathway during influenza vaccination enhances germinal center reactions, T follicular helper cell induction and, provides dose-sparing effect and protective immunity.

Kulkarni RR1, Rasheed MA2, Bhaumik SK1, Ranjan P3, Cao W3, Davis C2, Marisetti K1, Thomas S4, Gangappa S3, Sambhara S5, Kaja MK6.

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Abstract

Pattern Recognition Receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type-I IFNs. Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway on antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens co-administered with 5' ppp-dsRNA, a RIG-I ligand, developed robust levels of hemagglutination inhibiting antibodies, enhanced germinal center reaction and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of RIG-I pathway was able to reduce the antigen requirement by 10-100 folds in inducing optimal influenza-specific cellular and humoral responses including protective immunity. The effects induced by 5' ppp-dsRNA were significantly dependent on type-I IFN and IPS-1 (adapter protein downstream of RIG-I pathway) signaling, but were independent of MyD88 or TLR3 mediated pathways. Our results show that activation of RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses and thus, indicate the potential utility of RIG-I ligands as molecular adjuvants for the viral vaccines.

STUDY IMPORTANCE STATEMENT:

The recently discovered RNA helicase family of RIG-I-like receptors (RLRs) is a critical component of host defense mechanisms responsible for detecting viruses and triggering innate anti-viral cytokines that help control viral replication and dissemination. In this study we show that the RLR-pathway can be effectively exploited for enhancing adaptive immunity and protective immune memory against viral infection. Our results show that activation of RIG-I pathway along with influenza vaccination programs the innate immunity to induce qualitatively and quantitatively superior protective adaptive immunity against pandemic influenza viruses. More importantly, the RIG-I activation at the time of vaccination allows induction of robust adaptive responses even at sparing vaccine antigen doses. These results highlight the potential utility of exploiting RIG-I pathway for enhancing viral vaccine specific immunity and have broader implications for designing better vaccines in general.