Deficiencies in current tuberculosis (TB) immunodiagnostics pipeline demand new approaches to control TB.Because the balance in key pro-and anti-inflammatory cytokines production could determine Mycobacterium Tuberculosis (MTb) infection outcome, this study aimed to determine the patterns of MTb-specific antigen-stimulated Interferon-gamma (IFN-y) and Interleukin-10 (IL-10) production in different clinical forms of MTb infection and to evaluate their concomitant changes during anti-TB treatment (ATT). Overall, 84 BCG-vaccinated HIV-negative adults, consisting of 25 Healthy Community Controls (HCC), 27 Latent Tuberculosis Infection (LTBI) cases, and a cohort of 32 Acute Pulmonary Tuberculosis (APTB) patients were investigated for IFN-y and IL-10 responses at enrollment (base-line) and during ATT at 2-month (ATT1) and 6-month (ATT2). At enrollment, groups didn't differ significantly in age, gender, or CD4+ T counts but differed in the other socio-demographics, and hematological parameters, p<0.05. Base-line Sandwich ELISA -measured IFN-y responses were significantly higher in HCC (223.50±58.11pg/ml) compared with LTBI (128.82±41.81pg/ml) and APTB (47.82±22.05pg/ml), p<0.0001 in each case. During treatment, IFN-y levels increased significantly at ATT1 (125.37±16.09pg/ml) and ATT2 (203.35±23.24pg/ml), p<0.0001. Conversely, base-line IL-10 responses increased significantly in APTB (17.53±6.30pg/ml), compared with LTBI (10.71±2.39pg/ml) and HCC (7.49±2.02pg/ml), P<0.0001, but declined significantly at ATT1 (10.54±2.25pg/ml) and ATT2 (5.25±1.45pg/ml), P=<0.0001. Cytokines response combination ratio showed: 'High' HCC, 'Intermediate' LTBI, or 'Low' APTB ratio that increased during successful ATT; the two identified MDR-TB patients recorded fluctuating but constantly low ratio during ATT. These results demonstrate the immunocompetence of MTb-exposed adults, and that IFN-y and IL-10 cytokines cross-regulate, and strongly suggest a shift toward IFN-ymediated pro-inflammatory host immune phenotype during effective control of MTb infection. The IFN-y/IL-10 response ratio is a novel potential immunological biomarker to assess if MTb infection is going to resolve, result in latency, progress to TB; or become drug-resistant.