IL-2 produced by memory CD4 T cells synergizes with influenza A virus to amplify detrimental lung inflammation (IRC10P.404)

Abstract

Abstract Memory CD4 T cells capable of producing IL-2 in addition to IFNγ are often more effective at combating pathogens than those producing IFNγ alone. The impact of IL-2 on protective memory responses, however, is not well defined. To test if IL-2 contributes to memory CD4 T cell protection, we transferred wild type or IL-2-deficient memory CD4 T cells to unprimed mice and challenged with lethal doses of influenza A virus (IAV). We find comparable expansion of both donor populations and kinetics of viral clearance in both recipients. Strikingly, recipients of IL-2-deficient cells exhibit reduced weight loss, improved lung function, and earlier recovery. The improved outcome in recipients of IL-2-deficient memory cells correlates with significantly tempered inflammatory responses. To more directly assess the pro-inflammatory capacity of IL-2, we administered IL-2: anti-IL-2 antibody complexes targeting delivery to cells expressing distinct IL-2 receptors. IL-2 administration dramatically up-regulates a remarkably broad array of inflammatory mediators systemically and particularly in the lung. Multiple adaptive and innate cell populations contribute. IL-2 administration rapidly impaired lung function in unprimed animals and synergized with IAV infection to cause lethal lung damage. Our findings highlight that IL-2 produced by memory CD4 T cells can contribute to pulmonary inflammation during protective responses and have implications for improving IL-2 based therapies.