QuantiFERON-TB Gold Plus CD8+ T cell responses in contacts with tuberculosis disease and recent tuberculosis infection

The QuantiFERON-TB Gold Plus (QFT-Plus) replaced the QuantiFERON-TB Gold in-tube (QFT-GIT) in 2016 to increase assay sensitivity, based on the role of <i>Mycobacterium tuberculosis</i>-specific CD8+ T cells in the host response to tuberculosis infection (TBI). The QFT-Plus incorporates a fourth tube (TB2 tube) in addition to the TB antigen tube of the QFT-GIT (TB1 tube). The TB2 tube contains shorter peptides from early secretary antigenic 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) to stimulate CD8+ T cells as well as long peptides contained in the TB1 tube. Evidence that <i>Mycobacterium tuberculosis</i>-specific CD8+ T cells preferentially recognize heavily infected cells has generated interest in the QFT-Plus CD8+ T cell response (taking TB2-TB1 interferon-gamma [IFN-γ] >0.6 IU/mL as a threshold for CD8+ response) as a marker for TB disease and for recent TBI. We retrospectively analyzed the CD8+ responses in the QFT-Plus results of contacts screened at the Singapore TB Contact Clinic from January 2018 to October 2018. We found significantly higher proportions of contacts with TB2-TB1 IFN-γ >0.6 IU/mL among those with TB disease (28.8% vs 12.6%, <i>P</i> < 0.0001) and Stringent Converters (23.3% vs 12.6%, <i>P</i> < 0.0001) compared to All Others with TBI. Median TB2-TB1 IFN-γ values were also significantly higher in those with TB disease (0.13 vs 0.06 IU/mL, <i>P</i> < 0.0001) and Stringent Converters (0.17 vs 0.06 IU/mL, <i>P</i> = 0.036) compared to All Others with TBI. Our findings add to the evidence that the CD8+ response measured by the QFT-Plus assay may predict TB disease and recent TB infection.IMPORTANCEEvidence that <i>Mycobacterium tuberculosis</i>-specific CD8+ T cells preferentially recognize heavily infected cells has generated interest in the QuantiFERON-TB Gold Plus (QFT-Plus) CD8+ T cell response as a marker for tuberculosis (TB) disease and for recent TB infection. Taking TB2-TB1 interferon-gamma >0.6 IU/mL as a threshold for CD8+ response, we found CD8+ T cell response to be associated with TB disease and stringent QFT-Plus conversion in a cohort of contacts screened under our country's national program. This adds to the evidence for the potential utility of this marker to identify persons who would benefit from further investigations for TB disease and those with recent infection who would be candidates for TB preventive treatment.