High frequencies of Caspase-3-expressing M. tuberculosis-specific CD4 T cells are associated with active tuberculosis

Abstract

Abstract Background The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluations and detection of Mycobacterium tuberculosis (Mtb) in the patients’ sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes 3–6 weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that frequencies of Mtb-specific CD4+IFN-g+ T cells expressing caspase-3 would decrease following anti-TB treatment. Caspase-3, a member of cysteine proteases’ family, is highly expressed in CD4 effector T cells and has been shown to regulate T cell activation, cell cycle entry, proliferation and apoptosis. Methods Using polychromatic flow cytometry, we evaluated the expression of the active form of caspase-3 on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) (n=22), ATB (n=18), and from ATB patients undergoing anti-TB treatment (n=7). Results Frequencies of Mtb-specific IFN-g+CD4+ T cells that expressed active caspase-3 were higher in individuals with ATB compared to those with LTBI suggesting that apoptotic pathways are operant during pulmonary ATB. This marker also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. Conclusion We have identified caspase-3 on Mtb-specific CD4+ T cells as a marker that distinguishes ATB and LTBI and may provide a tool for monitoring treatment response and cure.