Subunit Vaccine-Elicited Effector-Like Memory CD8 T cells Protect Against Listeriosis

Development of T-cell-based subunit protein vaccines against diseases, such as AIDS, tuberculosis and malaria remains a challenge for immunologists. Here, we have evaluated whether cross-presentation induced by nanoemulsion adjuvant Adjuplex (ADJ), can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke protective systemic CD8 T cell-based immunity to Listeria monocytogenes (LM). Vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by migratory and resident dendritic cells and up-regulated CD69 expression on B and T lymphocytes in draining lymph nodes. By virtue of its ability to engage BATF3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into a distinct subset of granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided highly effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ limited the magnitude of ADJ-induced CD8 T cell memory and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to listeriosis. ImportanceTo date, the most effective vaccines primarily provide protection by eliciting neutralizing antibodies, while development of T-cell-based subunit vaccines against infectious diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Axiomatically, engagement of multiple innate immune receptors early in the response might be key to programming effective immunity. Hence, there is an impetus to develop combination adjuvants that engage multiple innate signaling pathways and additionally promote cross-presentation to stimulate CD8 T-cell immunity. Here, we show that a nano-emulsion adjuvant ADJ alone elicits effector-like memory CD8 T cells and provides highly effective immunity to listeriosis; combining ADJ with TLR agonists, including CpG and GLA, compromised T cell immunity to LM. In summary, this study provided fundamental insights into the effects of combining innate immune signaling with nano-emulsion adjuvants on memory T cell differentiation and protective immunity. These findings are expected to have implications in the use of combination adjuvants to develop subunit vaccines that engender systemic CD8 T-cell immunity to intracellular pathogens.