The authors observed that influenza virus infection of mice that had been primed with a heterosubtypic strain of influenza virus resulted in higher levels of innate inflammatory cytokines and chemokines — tumour necrosis factor (TNF), interleukin-1α (IL-1α), IL-1β, IL-6, IL-12, interferon-γ (IFNγ), CXC-chemokine ligand 1 (CXCL1), CXCL9, CXCL10 and CC-chemokine ligand 2 (CCL2) — early after infection compared with influenza virus-infected naive mice. The transfer of total CD4+ T cells from primed mice to naive mice or the transfer of either in vitro- or in vivo-generated memory CD4+ T cells induced similar increases in these inflammatory factors, indicating that memory CD4+ T cells enhance innate inflammatory responses early after influenza virus infection. The enhanced inflammatory response correlated with lower viral titres on day 3 after infection. Furthermore, memory T helper 1 (TH1)- and TH17-polarized, but not TH2-polarized or unpolarized, cells could induce innate cytokine and chemokine production and decrease viral titres following virus infection.
To assess the mechanisms involved, the authors used several knockout mouse strains and found that the response mediated by memory CD4+ T cells was independent of their production of IFNγ, TNF or CCL3. Further analysis showed that, in the lung, only memory CD4+ T cells upregulated the expression of the early activation marker CD69 and that activation of these cells in the lung (and not in the draining lymph node) was sufficient to enhance innate inflammatory mediator production. Memory CD4+ T cell activation depended on the recognition of antigen presented by CD11c+ antigen-presenting cells (APCs), but the response was shown to be independent of the activation of the main pathogen recognition pathways (through the use of type I IFN receptor-deficient and MYD88- and TRIF-deficient mice). Furthermore, innate inflammatory cytokine and chemokine production could be induced in the presence of the cognate antigen in the absence of infection.
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