TGF-β-mediated inhibition of IFN-γ production by Mycobacterium tuberculosis-specific T cells in the infected lung

Tuberculosis (TB) is a major global health problem killing over one million people every year. The emergence of multi and extremely-drug resistant (MDR and XDR) strains of Mycobacterium tuberculosis (Mtb) has made treatment difficult and has spurred interest in developing host-directed immunotherapeutics. A critical roadblock is our failure to understand how Mtb escapes eradication despite an apparently robust adaptive immune response. Interferon-γ (IFN-γ) producing CD4 T cells are critical for immunity, yet their abundance in the blood does not correlate with protection to TB, suggesting that their activity may be blocked locally at the primary site of infection in the lung. A leading candidate for IFN-γ suppression in the lung is transforming growth factor-β (TGF-β), a multifunctional cytokine that is capable of inhibiting IFN-γ. TGF-β is produced in excess at sites of active Mtb infection in both murine and human TB. Neutralization of TGF-β improves T-cell responses of active TB patients in vitro , but the extent of its role during in vivo TB is unknown. Here, we generated mixed bone marrow chimeras using WT mice and mice with a T cell-specific conditional deletion of TGF-β receptor II (dLck-Cre:TGFbRII fl/fl ). Mtb-specific TGF-βRII knockout cells outcompeted their WT counterparts and exhibited increased IFN-γ production during Mtb infection. Furthermore, Mtb-infected dLck-Cre:TGFbRII fl/fl mice had decreased bacterial loads early during infection. Finally, two pharmacological inhibitors of TGF-β signaling lowered the bacterial loads of lungs from Mtb-infected mice both early and late during infection. Targeting TGF-β may pave the way for new host-directed immunotherapeutics for TB.