TLR3 and TLR7/8 agonists improve immunization outcome in nicotine exposed mice through different mechanisms.

• Nicotine compromises humoral response to a protein antigen mixed with Alum. • Nicotine compromises cellular response to a protein antigen mixed with TLR4 agonist. • TLR3 or TLR7/8 agonist diminishes the adverse effects of nicotine on immunization. • The increased adjuvanticity of TLR3 agonist is not dependent on DC-NK cross-talk. • The increased adjuvanticity of TLR7/8 agonist is dependent on DC-NK cross-talk. It is known that cigarette smoke compromises the immune system and increases the risk of vaccine-preventable diseases. We reported that nicotine, the immunosuppressive component of cigarette smoke, disrupts the functional properties of DC and DC crosstalk with NK cells, which is pivotal in the initiation of immune responses to vaccines. We also showed that select TLR agonists could reduce the degrading effects of nicotine on DC-NK mediated immune responses in vitro. In this study, we further investigated the magnitude and mechanism of immune responses to a protein antigen formulated with alum or TLR agonists using WT, NK-depleted, and IFN-γ deficient mice exposed to nicotine. We found that R848 followed by Poly(I:C) acted as the most effective adjuvants to increase the percentage and number of IFN-γ-producing effector NK cells in the lymph nodes of immunized mice. In addition, we observed that the protein antigen formulated with Poly(I:C) or R848 improved the antigen-specific immune response in nicotine-exposed mice through NK-independent and -dependent mechanisms, respectively. These findings extend our understanding of the hyporesponsiveness of smokers to vaccines and provides the means to increase the efficacy of vaccines in this large population. [Display omitted] [ABSTRACT FROM AUTHOR]