CD137 is a Useful Marker for Identifying CD4+ T Cell Responses to Mycobacterium tuberculosis

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.