Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80–90%) against lethal murine salmonellosis, in comparison with a moderately protective (40–50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity. Author summary: Salmonella enterica infections exemplify the immunological challenges posed by intracellular bacterial pathogens, for which there are often limited or no effective vaccines and antimicrobial resistance is rapidly on the rise. A common signature among these infections is a strong dependence on CD4+ T cell responses for host immunity, although how such responses can be effectively induced in a vaccine setting remains a key challenge. Using two live-attenuated vaccines that offer distinct levels of protection against lethal salmonellosis in a murine model, we investigated what properties of vaccine-induced immune responses can be targeted for improving vaccine efficacy. Our data show that the longevity of activated CD4+ T cells in lymphoid and non-lymphoid organs is closely linked with vaccine efficacy. At the cellular level, we have shown that CD11b+Ly6GnegLy6Chi inflammatory monocytes play an important role in stimulating antigen-specific CD4+ T cells through antigen presentation mechanisms, as well as the production of CXCL9 and IL-12. Since our data suggest that acute inflammation is beneficial for optimising vaccine-induced T cell immunity, considerations should be given to preserving the targets of inflammatory signalling pathways as a means for improving vaccine efficacy in future development. [ABSTRACT FROM AUTHOR]