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

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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE266006 | GEO | 2025/02/24

REPOSITORIES: GEO