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.
Highlights
The influenza virus belongs to the family Orthomyxoviridae, and is a negative-sense single-strandedRNA virus
To clarify the effects of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) as a mucosal adjuvant, we focused on early immune responses involving cytokine expression, cell activation, and germinal center (GC) formation in Nasal-associated lymphoid tissue (NALT) after intranasal inoculation with both vaccine and adjuvant in this study
Cells prepared from NALT, lymph nodes (LNs), and spleens were blocked with anti-CD16/CD32 Ab (93) and stained with the following fluorescence-labeled Abs; anti-B220 (RA3-6B2), anti-CD45 (30-F11), anti-CD19 (MB19-1), anti-IgA, anti-CD4 (GK1.5), anti-CD8α (53-6.7), anti-CD11c (N418), anti-CD11b (M1/70), anti-CD80 (16-10A1), anti-CD86 (GL1), anti-CD69 (H1.2F3), anti-CD3 (145-2C11), anti-programmed cell death (PD)-1 (RMP1-30), anti-C-X-C chemokine receptor (CXCR)5 (L138D7), anti-Fas (Jo2), anti-GL7 (GL7), and anti-B cell activating factor (BAFF) (121,808)
Summary
The influenza virus belongs to the family Orthomyxoviridae, and is a negative-sense single-stranded. It is required to develop effective vaccines and adjuvants which strongly induce IgA in the nasal and respiratory mucosa to prevent epidemics of influenza virus. The response was toll-like receptor (TLR) 3-dependent [8] It is unclear how other mucosal adjuvants affect immune cells in NALT. To clarify the effects of cGAMP as a mucosal adjuvant, we focused on early immune responses involving cytokine expression, cell activation, and germinal center (GC) formation in NALT after intranasal inoculation with both vaccine and adjuvant in this study. Following i.n. vaccination, cGAMP strongly promoted STING-dependent activation of immune cells and formation of GCs. Enhancement of Ig production by cGAMP was not abolished in type I IFN receptor A (IFNAR)-defective mice, indicating that the adjuvanticity of cGAMP is independent of the IFN pathway
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