Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to combustion generated radical containing ultrafine particulate matter.

Abstract

Abstract Exposure to elevated levels of particulate matter (PM) is associated with adverse respiratory health and increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Our previous studies demonstrated combustion derived PM (CDPM) induced immunosuppression allowing for enhanced influenza disease severity and mortality in neonatal mice. Current studies are aimed at understanding the underlying mechanisms. Neonatal mice (3 day old) were acutely exposed to Air or DCB230 (CDPM), and infected with influenza virus (Flu), Air/Flu and DCB/Flu respectively. Pulmonary T cell profile and immunosuppressive cytokines were analyzed. At 10 days-post exposure, a significant increase in pulmonary Tregs and IL10 coinciding with decrease in protective T helper 1 (Th1) and cytotoxic T cell (Tc1) responses was observed in DCB/Flu mice compared to Air/Flu mice. Further, depletion of Tregs (using anti-CD25 antibody) in DCB mice prior to flu infection increased both Th1 and Tc1 cells, whereas adoptive transfer of DCB-induced Tregs into Air mice and later infection with flu suppressed these responses. To elucidate the role of IL10 in DCB/Flu mice, Air exposed neonatal mice were treated with recombinant IL10 (rIL10) and subsequently infected with flu (rIL10/Flu). rIL10/Air/Flu mice had increased morbidity and pulmonary viral load compared to Air/Flu mice, whereas, IL10 deficient DCB/Flu mice exhibited reduction in pulmonary viral load and morbidity compared to wild-type mice indicative of enhanced protection against flu. Together, these studies demonstrate that PM- induced Tregs and their effector cytokine, IL10, suppress adaptive T cell responses leading to increased influenza severity in infected neonatal mice.