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

Evelyn Chang, Kelly Cavallo and Samuel M. Behar ()
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Evelyn Chang: Morningside Graduate School of Biomedical Sciences
Kelly Cavallo: University of Massachusetts Chan Medical School
Samuel M. Behar: Morningside Graduate School of Biomedical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57819-1

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