Principal Investigator, Proteomics Lab, Head of Proteomics and Metabolomics Facility, IFOM ETS-The AIRC institute of Molecular Oncology, Milan, ITALY
T cell phenotypes in M. tuberculosis ‘resisters’ correlate with bacterial control
Host: D. KUKumarMAR
A subset of individuals with a high probability of exposure to M. tuberculosis (M.tb)
appears to ‘resist’ infection, as demonstrated by serially negative tuberculin skin test
(TST) or IFN-γ release assay (IGRA) results. While these ‘resisters’ (RSTR) display IFN-γ-
independent T cell responses to the M.tb-specific antigens ESAT-6 and CFP-10, it is
currently unknown whether specific T cell functional programs are associated with this
clinical outcome. We used multi-modal single-cell RNA and TCR sequencing to compare
the phenotypes and functions of M.tb-specific T cells between RSTRs and matched
controls with ‘latent’ M.tb infection (LTBI). M.tb-specific T cells were clonally expanded
in both RSTRs and LTBIs, confirming the priming of adaptive immune responses after
M.tb exposure. However, M.tb-specific T cells derived from RSTRs showed an early
differentiation phenotype as well as enrichment of Th17-like transcriptional programs
compared to LTBIs, which were characterized by Th1*-like effector programs. These
results were internally validated in an independent set of RSTRs and LTBIs using flow
cytometry and multiplex cytokine analysis. Additionally, we found that these IFN-γ-
independent CD4 T cell phenotypes correlated with bacterial control in published non-
human primate studies. Together, these data suggest that ‘resisters’ may successfully
control M.tb after exposure and immune priming and establish a set of T cell biomarkers
to facilitate further study of this important clinical phenotype.
International Seminar Programme
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