Increased IFN-γ–production by CD4 T cells exacerbates pulmonary Mtb infection and leads to the early host mortality, despite enhancing bacterial control in the spleen.

<p>RAG1 KO mice were infected with Mtb 7 days earlier and reconstituted with CD4 T cells from uninfected donors at increasing ratios of either WT or ARE-Del CD4 T cells mixed with IFN-γ KO CD4 T cells (<b>A</b>). All mice received the same total number of donor CD4 T cells, as only the fractions of IFN-γ–producing CD4 T cells varied (either WT or IFN-γ–overproducing). On day 42 IFN-γ concentrations in the lung homogenates (<b>B</b>) and bacterial load in the tissues were measured (<b>C</b>). Data are representative of two independent experiments (n = 5/group/experiment). (<b>D</b>) A mixture of WT and ARE-Del CD4 T cells (at 1:1 ratio) were co-transferred into day-7 infected TCRα KO mice, and on day 60 IFN-γ production by donor CD4 T cells was measured by DrxICS. Data are pooled from two independent experiments (n = 6/experiment) and each connecting line represents an individual animal. ****, <i>P</i><0.0001 (<b>E</b>) Correlation between IFN-γ levels and bacterial numbers in the lungs of RAG1 KO mice. Data shown are replotted from the values shown in (<b>B and C</b>) to illustrate the correlation. (<b>F</b>) TCRα KO mice were infected with Mtb 7 days before and received with WT, ARE-Del or a 1:1 mixture of WT and ARE-Del naïve CD4 T cells and mouse survival was monitored. Data are representative of three independent experiments. (n = 4-5/group/experiment). **, <i>P</i><0.002; compared to control group received WT CD4 T cells alone.