Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-Resistant Tuberculosis Treatment

Rationale: The advent of extensively drug-resistant (XDR) tuberculosis (TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host-directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend on understanding the host immune response in XDR-TB, which hitherto remains unexplored. Objectives: To determine the host immunological profile in patients with XDR-TB, compared with drug-sensitive TB (DS-TB), using peripheral blood and explanted lung tissue. Methods: Blood and explanted lung tissue were obtained from patients with XDR-TB (n = 31), DS-TB (n = 20), and presumed latent TB infection (n = 20). T-cell phenotype (T-helper cell type 1 [Th1]/Th2/Th17/regulatory T cells [Tregs]) was evaluated in all patient groups, and Treg function assessed in XDR-TB nonresponders by coculturing PPD-preprimed effector T cells with H37Rv-infected monocyte-derived macrophages, with or without autologous Tregs. Mycobacterial Measurements and Main Results: Patients failing XDR-TB treatment had an altered immunophenotype characterized by a substantial increase in the frequency (median; interquartile range) of CD4(+)CD25(+)FoxP3(+) Tregs (11.5%; 5.9-15.2%) compared with DS-TB (3.4%; 1.6-5.73%; P, 0.001) and presumed latent TB infection (1.8%; 1.2-2.3%; P = 0.001), which was unrelated to disease duration. Tregs isolated from patients with XDR-TB suppressed T-cell proliferation (up to 90%) and subverted containment of H37Rv-infected monocyte-derived macrophages (by 30%; P = 0.03) by impairing effector T-cell function through a mechanism independent of direct cell-to-cell contact, IL-10, TGF (transforming growth factor)-beta, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Conclusions: Collectively, these data suggest that Tregs may be contributing to immune dysfunction, and bacterial persistence, in patients with XDR-TB. The relevant cellular pathways may serve as potential targets for immunotherapeutic intervention.