Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis

Abstract

Development of T-cell-based subunit protein vaccines against diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Here, we have identified a nano-emulsion adjuvant Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes (LM). We further evaluated whether cross-presentation induced by ADJ, can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to LM. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and up-regulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided 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 reduced the number of ADJ-induced memory CD8 T cells 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 LM, a model intracellular pathogen.

Coimmunization with Preerythrocytic Antigens alongside Circumsporozoite Protein Can Enhance Sterile Protection against Plasmodium Sporozoite Infection

“…Carbomer-based compounds (acrylic acid polymers) are under investigation as synthetic adjuvants, due to their ability to stimulate robust immunity and inherent low toxicity ( 25 ). They have been extensively studied in many preclinical models for vaccines against numerous pathogens, including parasites, viruses, and fungi ( 26 – 29 ).…”

Vaccine adjuvants to engage the cross-presentation pathway

“…However, unexpectedly, we found that impaired accumulation of monocytes induced by CCR2 deficiency did not significantly affect the activation and expansion of antigen-specific CD8 T cells in spleens or lungs. These findings suggest that monocytes are not required for ADJ-driven antigen cross-presentation and/or for driving the accumulation of antigen-specific CD8 T cells in vivo ( 220 , 222 ). Interestingly however, loss of pulmonary monocytes in CCR2 -/- mice led to substantive increase in the total numbers of tissue-resident memory CD8 T cells in lungs of vaccinated mice ( 220 ).…”

“…Other studies from our group demonstrated that ADJ robustly stimulates systemic antigen-specific CD4 and CD8 T-cell responses to subunit protein antigen, and protected against vaccinia virus, Listeria monocytogenes (L. monocytogenes ) and respiratory fungal infections ( 221 , 223 , 234 ). Specifically, upon subcutaneous vaccination of mice, ADJ elicited effector CD8 T cells that differentiated into a distinct subset of granzyme B-expressing CD27 LO ‘effector-like’ memory CD8 T cells, which provided highly effective immunity to intracellular bacteria L. monocytogenes in spleen and liver ( 222 ). Additionally, we have reported that ADJ, in combination with TLR agonists CpG and GLA, stimulated high numbers of tissue resident memory CD4 and CD8 T cells in the respiratory tract and protected against antigenically distinct strains of influenza viruses ( 218 – 220 ).…”

“…Like vaccine adjuvants, various innate immune cells, including monocytes, neutrophils, and conventional dendritic cells, are rapidly recruited within 24-48 hours of intradermal, intraperitoneal, and intranasal vaccination of ADJ-containing vaccines at the injection sites ( 219 , 222 , 230 ). CD8 T cell response induced by mucosal or parenteral administration of vaccine antigens formulated in ADJ was ablated in BATF-3-deficient mice ( 220 , 222 ). These data suggest that stimulation of CD8 T cell responses to subunit vaccine antigens formulated in ADJ requires cross-presentation, presumably by BATF3-dependent conventional migratory DCs.…”