IFN-γ secretion by memory CD4 T cells mediates immunopathology during secondary influenza infection by enhancing local lymphoid responses (105.6)

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Abstract During secondary flu infection, flu-specific memory CD4 T cells induce protection and exacerbate cellular infiltration and inflammation. We investigated the role of IFN-γ production by memory CD4 T cells in the development of lung immunopathology during secondary flu infection by generating and analyzing in vivo responses of memory IFN-γ deficient CD4 T cells. We found similar precursor frequencies of flu-specific CD4 T cells after primary influenza infection of IFN-γ-/- and WT mice, with IFN-γ-/- memory CD4 T cells producing rapid IL-2 and TNF-α compared to the predominant IFN-γ and IL-2 production by WT memory CD4 T cells. Adoptive transfer of equal numbers of flu-specific WT and IFN-γ-/- memory CD4 T cells into naïve mouse hosts resulted in increased pulmonary infiltration and hypoxia 7 days after flu challenge only in recipients of WT memory CD4 T cells. Notably, flu-specific WT cells in the MLN exhibited increased expansion and activation compared to flu-specific IFN-γ-/- CD4 T cells. Furthermore, lung homogenates from recipients of WT memory CD4 T cells had significantly higher levels of the chemokines, CCL4 and CCL5, compared to recipients of IFN-γ-/- CD4 T cells. These findings suggest that IFN-γ secretion by memory CD4 T cells acts as a potential switch for the development of immunopathology, possibly by recruiting DCs to the lung, which in turn migrate to the MLN for activation and priming of large numbers of CD4 and CD8 cells