Improved tools are required to study immunopathogenesis of tuberculosis (TB). Mycobacterium tuberculosis antigen-stimulated T cell-based assays can detect TB but are less effective when responses are compromised such as in severe disease. We investigated immune responses to M. tuberculosis whole sonicate (MTBs), recombinant antigens ESAT6 and CFP10 in whole blood cells of healthy endemic controls (EC, n=42) and patients with pulmonary (PTB, n=36) or extrapulmonary (ETB, n=41) disease. Biomarkers of T cell activation (IFNγ) or modulation (IL10) and chemokines, CXCL9, CXCL10 and CCL2, secretion were measured. MTBs, ESAT6 and CFP10 all induced IFNγ responses in TB. ESAT6-induced IFNγ was elevated in TB as compared with EC. MTBs stimulated the highest IFNγ levels but did not differentiate between TB and EC. However, MTBs-induced CXCL10 (P=0.004) was reduced, while IL10 (P<0.001) was raised in TB as compared with EC. Between sites, MTBs-induced CCL2 (P=0.001) and IL10 secretion was higher in PTB than ETB (P<0.001). In comparison of disease severity, MTBs-induced IFNγ (P=0.014) and CXCL10 (P=0.022) levels were raised in moderate as compared with far advanced PTB. In ETB, MTBs-induced IL10 levels were greater in less-severe (L-ETB) than in severe disseminated (D-ETB) cases, P=0.035. Within the L-ETB group, MTBs-induced IFNγ was greater in patients with tuberculous lymphadenitis than those with pleural TB (P=0.002). As immune responses to MTBs were differentially activated in TB of different sites and severity, we propose the utility of MTBs-induced IFNγ, CXCL10 and IL10 as biomarkers in TB.