Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation.pdf (2.38 MB)
Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation.
journal contributionposted on 2019-08-21, 10:39 authored by KK McKinstry, F Alam, V Flores-Malavet, MZ Nagy, S Sell, AM Cooper, SL Swain, TM Strutt
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 memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. 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 to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.
The following funding agencies supporting this work: T.M.S. was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, R21 AI117457-01A (https://www.niaid.nih.gov) and US Department of Health and Human Services Eunice Kennedy Shriver National Institute of Child Health and Human Development R21 HD093948-01A1 (https://www.nichd.nih.gov). S.L.S. was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U10AI109858 Project 2, (https://www.niaid.nih.gov), and K.K.M. was supported by the American Heart Association, 14SDG18600020 (https://www.heart.org/en/professional/quality-improvement/quality-research-and-publications/young-investigator-research-opportunities). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
CitationPLoS Pathogens, 2019, 15(8): e1007989.
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation
- VoR (Version of Record)