Chetan SHESHANDRI

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.

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