Antigen-specific T Cell Activation Distinguishes Between Recent and Remote Tuberculosis Infection

Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion 1 year) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+TNF+ Mycobacterium tuberculosis-specific and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease, and unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (non-progressors) or who progressed to microbiologically-confirmed disease (progressors). In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n=25) and QuantiFERON-TB+ (n=47) individuals (area under the ROC curve and 95% confidence intervals: 0.94; 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n=20) and persistent (n=22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n=19, 0.99; 0.96-1.00); and tuberculosis progressors (n=22) and non-progressors (n=34, 0.75; 0.63-0.87). However, ΔHLA-DR MFI could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.