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.