Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by CD4 memory cells, a widely held indicator of their protective potential, impacts recall responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory cells are more effective on a per cell basis at combating IAV than wild-type memory cells marked by strong IL-2 production. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals that reduce T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 cells and improves the outcome of IAV infection in vaccinated mice. Using a reductionist model, we show that IL-2 drives rapid and extremely potent lung inflammation involving NK cells and neutrophils, which can synergize with sublethal IAV infection to promote acute morbidity and mortality. These results suggest that IL-2 production is dispensable for optimal protective CD4 T cell recall responses and that the lung environment is particularly sensitive to IL-2-induced inflammation.
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