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

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• Most Mycobacterium tuberculosis infections are contained, but some progress to active disease.
• The mechanisms underlying the failure of immune control during chronic tuberculosis remain unclear.

Purpose of the Study:

• To investigate the hypothesis that CD4 T cell dysfunction contributes to Mycobacterium tuberculosis recrudescence.
• To analyze T cell responses during chronic infection in a mouse model.

Main Methods:

• Utilized a reductionist model to assess antigen-specific T cells in C57BL/6 mice during chronic Mycobacterium tuberculosis infection.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze T cell populations in the lungs.

Main Results:

• Evidence of CD4 T cell senescence and exhaustion was observed in chronically infected mice.
• CD4 T cells upregulated coinhibitory receptors and exhibited reduced effector cytokine production.
• scRNA-seq revealed a limited number of polyfunctional CD4 T cells in the lungs.

Conclusions:

• T cell dysfunction, characterized by senescence and exhaustion, may permit Mycobacterium tuberculosis recrudescence.
• A potential feed-forward loop exists where increased bacterial load exacerbates T cell dysfunction, driving progressive disease.