cGAMP Promotes Germinal Center Formation and Production of IgA in Nasal-Associated Lymphoid Tissue

Abstract

Induction of immunoglobulin (Ig) A in the mucosa of the upper respiratory tract and the nasal cavity protects against influenza virus infection. Cyclic dinucleotides (CDNs) are used as mucosal adjuvants to enhance the immunogenicity of intranasal influenza hemagglutinin (HA) vaccines. The adjuvant activity of 2′3′ cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) on Ig production was investigated in nasal-associated lymphoid tissue (NALT), serum of wild-type C57BL/6J, and stimulator of interferon genes (STING)-deficient mice, which do not recognize cGAMP. Mice were vaccinated intranasally with a HA vaccine with or without the cGAMP adjuvant. IgA and IgG production, T-cell responses, germinal center formation, and cytokine expression in NALT were assayed. cGAMP enhanced IgA and IgG production, and promoted T-cell responses. Intranasal administration of cGAMP activated both NALT and systemic immune cells, induced a favorable cytokine environment for IgA induction, and promoted germinal center formation. The cGAMP effect was STING-dependent. Taken together, cGAMP as an HA vaccine adjuvant promoted a STING-dependent NALT environment suitable for the enhancement of IgA production.

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

“…Viral replication was also controlled more effectively in mice vaccinated with NP-p24 plus 2′3′-cGAMP relative to mice vaccinated with NP-p24 alone ( Figure 6D). Of note, mucosal and systemic HIV-1 Gag p24-specific IgA and IgG titers were very high in mice vaccinated with NP-p24 plus 2′3′-cGAMP, consistent with recent studies (17,18), but remained undetectable in mice vaccinated with NP-p24 alone (Supplemental Figure 5).…”

Innovative Mucosal Vaccine Formulations Against Influenza A Virus Infections

“…Another class of nucleotide-based adjuvant, CDN, exhibited comparable efficacy to poly (I:C) in enhancing the immunogenicity of mucosal IAV split or subunit vaccines in mice (114, 189–192). CDN are bacterial second-messenger molecules detected by the innate immune system via various sensors including STING (189). The inclusion of 2′,3′-cyclic-guanosine monophosphate-adenosine monophosphate (cGAMP) in i.n.…”

“…The inclusion of 2′,3′-cyclic-guanosine monophosphate-adenosine monophosphate (cGAMP) in i.n. H1N1 split vaccine stimulated the activation of innate and adaptive immunity in the NALT, the spleen and the DLN, and promoted GC formation in the NALT in a STING-dependent pathway (189). It resulted in an increase in specific serum and mucosal humoral responses and in systemic type 1/type 2/type 17 cellular immune responses, including higher frequency of IFN-γ-producing CD4 + and CD8 + T cells in the spleen (189).…”

“…H1N1 split vaccine stimulated the activation of innate and adaptive immunity in the NALT, the spleen and the DLN, and promoted GC formation in the NALT in a STING-dependent pathway (189). It resulted in an increase in specific serum and mucosal humoral responses and in systemic type 1/type 2/type 17 cellular immune responses, including higher frequency of IFN-γ-producing CD4 + and CD8 + T cells in the spleen (189). Other studies demonstrated that the addition of CDN to recombinant H5N1 HA or H1N1 NP subunit vaccines enhanced the magnitude and/or the breadth of the humoral and cellular anti-IAV immune responses in mice (190, 192).…”

Mucosal Immune Response in Nasal-Associated Lymphoid Tissue upon Intranasal Administration by Adjuvants

“…CDNs exert potent adjuvanticity on the vaccine effect, including Ig production, the T-cell response, and the formation of germinal centers, via the STING pathway [38, 45-47]. The adjuvanticity of c-di-GMP is more effective than that of cGAMP because it enhances antigen uptake by DCs and the selective activation of pinocytosis-efficient cells [38].…”