Antigen-specific CD4 T cell memory and functional kinetics during QuantiFERON test reversion
Authors: Cheleka Mpande, Virginie Rozot, Boitumelo Mositio, Mark Hatherill, Thomas J. Scriba and Elisa Nemes
Affiliation: South African Tuberculosis Vaccine Initiative, Div. of Immunology, Dept of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town.
Abstract: BCG revaccination of M.tb-uninfected adolescents was partially protective against sustained M.tb infection and associated with QuantiFERON (QFT) reversion. In animal models, tuberculin skin test reversion is associated with bacterial clearance. Understanding immunological kinetics associated with QFT reversion in humans could provide indirect evidence of reduced bacterial burden, and inform the interpretation of serial QFT results.
We compared groups of healthy adolescents (n»30 each), defined by four, 6-monthly QFT tests: QFT-reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent-positives (QFT+/+/+/+). We measured CFP10/ESAT6- or M.tb lysate-specific CD4 T cell memory (CD45RA, CCR7, CD27, KLRG1), activation (HLA-DR), and functional (IFN-g, IL-2, TNF) profiles by flow cytometry.
No longitudinal changes in the magnitude of CD4+ CFP10/ESAT6-specific IFN-g+, total Th1-cytokine+, major memory nor T cell activation profiles were observed in QFT-reverters. QFT-reverters exhibited an intermediate polyfunctional Th1 response which was higher than non-converters and lower than persistent-positives. Lower proportions of TSCM (CD45RA+CCR7+CD27+) -and early differentiated (CD45RA-) -IFN-g-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed upon reversion compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in QFT-reverters compared to persistent-positives.
These findings suggest that once M.tb-infection has been established, immunological memory is sustained upon QFT-reversion. Magnitude and differentiation of M.tb-specific Th1 cells in QFT-reverters are consistent with a low grade or controlled infection, but we found no strong evidence of bacterial clearance. QFT reversion in this cohort likely results from low immune responses that fluctuate around the assay cut-off.