Upregulation of CD137 on recently activated CD8⁺ T cells has been used to identify rare viral and tumour antigen-specific T cells from the peripheral blood. We aimed to evaluate the accuracy of CD137 for identifying Mycobacterium tuberculosis (Mtb)-reactive CD4⁺ T cells in the peripheral blood of infected individuals by flow cytometry and to investigate the characteristics of these CD137⁺ CD4⁺ T cells. We initially enrolled 31 active tuberculosis (TB) patients, 31 individuals with latent TB infection (LTBI) and 25 healthy donors. The intracellular CD137 and interferon-γ (IFN-γ) production by CD4⁺ T cells was simultaneously detected under unstimulated and CFP10-stimulated (culture filtrate protein 10, a Mtb-specific antigen) conditions. In unstimulated CD4⁺ T cells, we found that the CD137 expression in the TB group was significantly higher than that in the LTBI group. Stimulation with CFP10 largely increased the CD4⁺ T cell CD137 expression in both the TB and LTBI groups. After CFP10 stimulation, the frequency of CD137⁺ CD4⁺ T cells was higher than that of IFN-γ⁺ CD4⁺ T cells in both the TB and LTBI groups. Most of the CFP10-activated IFN-γ-secreting cells were CD137-positive, but only a small fraction of the CD137-positive cells expressed IFN-γ. An additional 20 patients with TB were enrolled to characterize the CD45RO⁺ CCR7⁺ , CD45RO⁺ CCR7^- and CD45RO^- subsets in the CD137⁺ CD4⁺ T cell populations. The Mtb-specific CD137⁺ CD4⁺ T cells were mainly identified as having an effector memory phenotype. In conclusion, CD137 is a useful marker that can be used for identifying Mtb-reactive CD4⁺ T cells by flow cytometry.

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