Abstract
Abstract It is recognized that cigarette smoke dampens the immune system and increases the risk of vaccine-preventable diseases. Studies suggest that combining more than one TLR agonists enhances the magnitude of immune responses to vaccination. We reported that TLR agonists acted in synergy and promoted human DC maturation, DC-NK crosstalk and ultimately naïve T cells polarization into effector Th1 and Tc1 cells. In this study, we studied whether the combination of TLR agonists could diminish the degrading effects of nicotine, the immunosuppressive component of cigarette smoke, on human DC-NK mediated effector T cell generation. We found that none of TLR agonists, single and combined, were able to diminish completely the adverse effects of nicotine on DCs. However, TLR3, TLR4, and TLR8 agonists acted as the most effective adjuvants to increase the expression levels of antigen-presenting, co-stimulatory molecules and production of cytokines by nicotine-exposed DCs (nicDCs). When combined, TLR3+8 and TLR4+8 synergistically optimized nicDC maturation and IFN-γ secretion from nicotine-exposed NK (nicNK) during co-cultures. Interestingly, in contrast to DC-NK-T, co-cultures of nicDC-nicNK-T treated with TLR3+8 or TLR4+8 agonists produced similar frequency of effector memory CFSE-CCR7− Th1 and Tc1 cells. However, the effector cells from TLR4+8 followed by TLR3+8 treated nicDC-nicNK-T co-cultures produced significantly more IFN-γ when compared with aluminum salt treated co-culture. Our data suggest that the addition of appropriate TLR agonists to vaccine formulation could potentially augment the vaccination outcome in smokers.
Published Version
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