CD4 T cell transcriptomics reveal novel diagnostic and mechanistic immune signatures of tuberculosis

Abstract As part of the Human Immune Project Consortium (HIPC) program, we are aiming to decipher CD4 T cell immune signatures of tuberculosis (TB) in the context of controlled (latent TB) and uncontrolled (active TB) infection. We found commonalities and differences in TB-specific CD4 T cell immune responses of latent TB vs active TB subjects. Both cohorts had higher frequency of peptide-reactive CD4 T cells compared to TB uninfected individuals, and showed strong upregulation of type I and type II interferon genes in response to antigen-specific in vitro stimulation. Conversely, we also detected differences in the transcriptome of CD4 T cells between latent vs active TB subjects that can inform us on TB-specific T cell immune signatures of controlled infection versus disease. In particular, active TB was associated with higher expression of genes associated with inflammation (TNF, IL-1 and TLR signaling) whereas latent TB was enriched for genes associated with metabolism, oxidative phosphorylation and neutrophil-mediated immunity. Looking at inter-individual variability, we also identified that some latent TB infected subjects showed similar expression patterns for a subset of genes to those with active TB, suggesting this molecular pattern might contain mechanistic and prognostic information on the risk of developing active TB. Overall, our approach has identified a plethora of TB-associated T cell immune signatures that allowed us to gain mechanistic insights into the key CD4 T cell components contributing to TB protective immunity. Additionally, our findings have the potential to be translated into new diagnostic and prognostic tools, in particular, identifying latent TB infected individuals at risk of developing active TB.