Protective role of γδ T cells in cigarette smoke and influenza infection

Abstract

Airborne pathogens commonly trigger severe respiratory failure or death in smokers with lung disease. Cigarette smoking compromises the effectiveness of innate immunity against infections but the underlying mechanisms responsible for defective acquired immune responses in smokers remains less clear. We found that mice exposed to chronic cigarette smoke recovered poorly from primary Influenza A pneumonia with reduced type I and II interferons (IFNs) and viral-specific immunoglobulins, but recruited gamma delta (γδ) T cells to the lungs that predominantly expressed interleukin 17A (IL-17A). Il-17a-/- mice exposed to smoke and infected with Influenza A also recruited γδ T cells to the lungs, but in contrast to wild type mice, expressed increased IFNs, made protective influenza specific antibodies, and recovered from infection. Depletion of IL-17A with blocking antibodies significantly increased T-bet expression in γδ T cells and improved recovery from acute Influenza A infection in air, but not smoke exposed mice. In contrast, when exposed to smoke, γδ T cell deficient mice failed to mount an effective immune response to Influenza A and showed increased mortality. Our findings demonstrate a protective role for γδ T cells in smokers and suggest that smoke-induced increase in IL-17A inhibits the transcriptional programs required for their optimal anti-viral responses.

Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine

“…To further examine the translational relevance of reduction of M1-associated markers, impaired macrophage responses to poly I:C, and surfactant dysregulation in mice exposed to ENDS vapor, we next assessed defenses against acute viral infection. We have previously shown that mice exposed to chronic cigarette smoke, before sublethal infection with influenza A, fail to mount the appropriate antiviral responses and exhibit increased morbidity (32). In a similar manner, mice were exposed to Air (control), chronic ENDS-vehicle (PG/VG), or ENDS-nicotine for 3 months and were subsequently challenged with the influenza A virus (45 TCID 50 /mouse).…”

“…All chemokine analyses were performed on BAL fluid supernatants using a ProcartaPlex Immunoassay (Thermo Fisher Scientific) for selected chemokines (CCL2, CCL3, CCL4 CCL5, CCL11, CXCL1, and CCL20). For the determination of antibody titers in the influenza study, the aforementioned supernatants were used for IgG-specific ELISAs (Southern Biotechnology) as previously described (32). For pulmonary surfactant-specific ELISAs, specifically SP-D (R&D Systems), BAL fluid was acquired as described above.…”

“…Influenza A infection. Mice were infected with influenza A/Hong Kong/8/68 (H3N2) (A/HK/68) following 3-month exposure to air or ENDS using previously described methods (32). Briefly, following 3 months of ENDS exposure, mice were infected with an aerosolized lethal (45 TCID 50 /mouse) or sublethal dose (20 TCID 50 /mouse) of A/HK/68.…”

“…Mouse model of conventional cigarette smoke and ENDS exposure. Mice were exposed to 4 Marlboro Red 100 cigarettes/day as previously described (27,32,58,59). Briefly, C57BL/6J mice (2-month-old females) were exposed to active smoke from Marlboro cigarettes.…”

“…Histopathological scoring. Hematoxylin-and eosin-stained (H&Estained) slides from influenza-infected mice were coded and scored as described previously (32). A blinded observer scored the tissue from 0 (absent) to 4 (severe) for the following parameters: interstitial and endothelial inflammation, bronchitis, edema, thrombi, and percentage of lung surface exhibiting diffuse inflammatory infiltrate according to previously published guidelines (62).…”