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Adjuvants are often essential additions to vaccines that enhance the activation of innate immune cells, leading to more potent and protective T and B cell responses. Only a few vaccine adjuvants are currently used in approved vaccine formulations in the United States. Combinations of one or more adjuvants have the potential to increase the efficacy of existing and next-generation vaccines. In this study, we investigated how the nontoxic double mutant Escherichia coli heat-labile toxin R192G/L211A (dmLT), when combined with the TLR4 agonist monophosphoryl lipid A (MPL-A), impacted innate and adaptive immune responses to vaccination in mice. We found that the combination of dmLT and MPL-A induced an expansion of Ag-specific, multifaceted Th1/2/17 CD4 T cells higher than that explained by adding responses to either adjuvant alone. Furthermore, we observed more robust activation of primary mouse bone marrow–derived dendritic cells in the combination adjuvant–treated group via engagement of the canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex. This was marked by a multiplicative increase in the secretion of active IL-1β that was independent of classical gasdermin D–mediated pyroptosis. Moreover, the combination adjuvant increased the production of the secondary messengers cAMP and PGE2 in dendritic cells. These results demonstrate how certain adjuvant combinations could be used to potentiate better vaccine responses to combat a variety of pathogens.

The severity and outcome of influenza virus infection are dependent on various host factors including sex. During the 1918 influenza pandemic, males succumbed to viral infections more than females. Following seasonal influenza vaccination, haemagglutination inhibition titers are significantly higher in females than males. Additionally, the Tlr7 gene that recognizes influenza viruses is located on the X chromosome, resulting in higher expression in females. It is not known whether sex influences non-lymphoid tissue residency of lymphocytes during influenza infection. To explore this, we infected male and female mice intratracheally with 20 PFU influenza virus (A/PR8/H1N1). No significant change was noted in weight loss; however, females displayed a higher survival rate and milder clinical disease nine days post-infection. Lungs of female mice contained greater numbers of influenza-specific tissue-resident CD4+ T-cells compared to males. To assess the role of extra-lymphoid tissues in tissue residency in both sexes, we infected male and female lymphotoxin-a knockout (LTa KO) splenectomized mice that resulted in a total lack of all lymphoid tissues. Physiological differences trended the same for both males and females, with no significant weight difference; however, LTa KO females generated more tissue-resident CD4+ T-cells, while males displayed greater numbers of tissue-resident CD8+ T-cells. Overall, females generated a stronger immune response in the absence of lymphoid tissues in response to the virus. Taken together, our data reveal a novel sex-based effect of viral infection on tissue-resident lymphocytes and non-lymphoid tissue immunity. Supported by a grant from the W.M. Keck Foundation