Detrimental Effects of B-Cell-Th17 Axis in Antiviral Immunity in Smokers. - Smokers are at increased risk for viral-induced respiratory failure and hospitalization. We have shown that cigarette smoking (CS) induces systemic inflammation characterized by increased interleukin 17A (IL-17A) expression in CD4 T helper (Th)17 cells in mice and humans. CS promotes Th17 cell differentiation in the lungs while reducing several key transcription factors critical in protecting against viral infection. Mice exposed to chronic CS and infected with influenza A virus (IAV) have increased IL-17A in the lungs, reduced flu-specific B cells, and increased mortality compared to controls. Consistently, in a prospective study, we have found that active smokers vaccinated against seasonal IAV have reduced flu-specific neutralizing antibody titers two months post-vaccination. Together, these findings indicate a strong link between smoking and reduced flu- specific memory B cell (Bmem) development. CD4 T follicular helper (Tfh) cells and dendritic cells (DCs) play a key role in mediating the selection and survival of B cells that differentiate into plasma cells, however, how CS changes their development or function remains unknown. Therefore, significant knowledge gaps include whether i) Tfh cells and DC numbers and/or function are perturbed in smokers with increased levels of IL-17A, and ii) B cell-Th17-axis impairs flu-specific antibody production and virus-specific Bmem development. Our central hypothesis states that CS increases IL-17A in the lungs which impairs the differentiation and/or function of Tfh subsets and DCs, decreasing protective immunity against IAV. We have assembled an outstanding team of physicians, immunologists, and bioinformatics to test our hypothesis with Specific Aims: Aim 1) Determine the mechanism of CS-induced loss of long-term protective flu-specific B cell immunity. Rationale: compared to controls, mice exposed to CS and IAV have increased Th17 cells in the lungs, reduced flu-specific antibodies, and blunted HA-specific B cell responses. This aim will test the hypothesis that active CS induces IL-17A in the lung that alters systemic and transcriptional factors required to produce protective Bmems. Aim 2) Determine flu-specific memory B cell function and transcriptomic changes in the lungs of smokers. Rationale: compared to controls, active smokers have increased Th17 cells and reduced flu-specific Bmems in the lungs. This Aim will test the hypothesis that ineffective expansion of flu-specific Tfh cell pool in the lung correlates with poor Bmem survival and lack of high-affinity antibodies against IAV in humans. Aim 3) Determine the mechanism involved in systemic immune responses to flu antigens in smokers. Rationale: compared to controls, active smokers show reduced neutralizing antibody titers following flu vaccination. This Aim will test the hypothesis that CS induces systemic changes to the immune cell transcriptome required to develop protective Bmems in response to seasonal flu vaccination. Impact: Unraveling the mechanisms for failure to develop protective antibodies against flu in smokers provides critical evidence for designing human clinical trials and testing new treatments for this at-risk population.
