Exhaustion of CD4⁺ T cells is associated with bacterial load in active tuberculosis patients

Immunity against TB largely relies on CD4⁺ T cells. The degree of T cell exhaustion is inversely associated with mycobacterial burden and can be partially reversed upon effective anti-tuberculosis therapy. However, the relationship between PD-1 expression and bacterial load remains incompletely defined. In this study, we sought to characterize PD-1 expression across distinct lymphocyte subsets in a well-characterized cohort of TB patients with quantified bacterial burden.

Suspected cases were prospectively enrolled in Beijing Chest Hospital between January and December 2023. Following predefined inclusion and exclusion criteria, 113 patients with confirmed tuberculosis were identified. Mycobacterial burden was quantified using the Xpert assay, and exhaustion of peripheral lymphocyte subsets was assessed by flow cytometry.

In TB patients who tested positive by Xpert, the frequencies of CD3⁺ T cells and NK cells were reduced, whereas CD4⁺ T cells and the CD3/NK ratio were elevated. Stratification by Xpert CT values further indicated that individuals with higher bacterial burdens exhibited a decline in circulating CD3⁺ T cells, accompanied by increases in CD4⁺ T cells and the CD3/NK ratio. Moreover, analysis of exhaustion markers revealed enrichment of CD3⁺PD-1⁺ and CD4⁺PD-1⁺ T cells in patients with high bacterial loads, with CD4⁺PD-1⁺ T cell abundance showing a significant inverse correlation with CT values.

In TB patients, mycobacterial burden was associated with alterations in T cell populations and functional exhaustion. Overall T cell counts were reduced, whereas CD4⁺ T cells were relatively elevated. Moreover, CD4⁺ T cell exhaustion positively correlated with mycobacterial load. These findings highlight the potential value of immunotherapeutic interventions in patients with high bacterial burdens and provide a theoretical rationale for incorporating host-directed strategies into future TB treatment regimens.