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

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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. We developed a reductionist model to assess antigen-specific T cells during chronic infection and found evidence of CD4 T cell senescence and exhaustion. In C57BL/6 mice, CD4 T cells upregulate coinhibitory receptors and lose effector cytokine production. Single cell RNAseq shows that only a small number of CD4 T cells in the lungs of chronically infected mice are polyfunctional. While the origin and causal relationship between T- cell dysfunction and recrudescence remains uncertain, we propose T cell dysfunction leads to a feed-forward loop that causes increased bacillary numbers, greater T cell dysfunction, and progressive disease.