Progressive CD4 T cell dysfunction is associated with bacterial recrudescence during chronic tuberculosis.

While most people contain Mycobacterium tuberculosis infection, some individuals develop active disease, usually within two years of infection. Why immunity fails after initially controlling infection is unknown. C57BL/6 mice control Mycobacterium tuberculosis for up to a year but ultimately succumb to disease. We hypothesize that the development of CD4 T cell dysfunction permits bacterial recrudescence. Transcriptomic analysis reveals that only a small proportion of CD4 T cells in the lungs of chronically infected mice are polyfunctional; most are hypofunctional. We developed a reductionist model to assess antigen-specific T cells during chronic infection and found evidence of senescence and exhaustion. In C57BL/6 mice, CD4 T cells upregulate inhibitory receptors and lose effector cytokine production. While the origin and causal relationship between T-cell dysfunction and recrudescence remains uncertain, we propose these factors promote a feed-forward loop that causes loss of T cell function, increased bacillary numbers, and the development of progressive tuberculosis. Overall design: Naïve ESAT-6 specific CD4 TCR transgenic (C7) T cells were isolated from spleens and lymph nodes of TCR transgenic mice and transferred intravascularly into TCRa KO mice. Mice were then infected with Mtb Erdman through the aerosol route 16-24 hours later. Parenchymal (CD45 IV Neg) C7 T-cells were then sorted from the lungs of infected mice at 4 and 25 weeks post-infection (wpi). RNAseq was performed on RNA isolated from sorted C7 T cells.