T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection

Abstract

Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two longitudinal cohorts, comprising 166 individuals with M. tuberculosis infection who progressed to either tuberculosis (n = 48) or controlled infection (n = 118). We found 24 T cell groups with similar TCR-β sequences, predicted by GLIPH2 to have common TCR specificities, which were associated with control of infection (n = 17), and others that were associated with progression to disease (n = 7). Using a genome-wide M. tuberculosis antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or in progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development.

Finding antigens for TB vaccines: the good, the bad and the useless

“…The findings revealed by Musvosvi et al 3 build on previous efforts using TCR sequences and structural features to infer the antigen specificity of T cells of interest. Advances in sequencing, structure determination and analysis platforms -such as GLIPH2 (Grouping of Lymphocyte Interactions by Paratope Hotspots) 5 , DeepTCR 6 and others 7 -have accelerated efforts to identify antigens that can be used as vaccine targets for infectious diseases, or even to identify TCR sequences that predict responses to cancer immunotherapy 7 .…”

“…PE13 is a member of a large protein family in the Mtb complex. Although the epitope identified by Musvosvi et al 3 is unique to PE13, the Mtb proteome includes nine other peptides in other PE proteins with >80% sequence similarity to this epitope, which prompts the question: might protection be a consequence of cross-recognition of multiple PE13-related proteins expressed by Mtb? CFP-10 is notable for its deletion from the existing BCG TB vaccine, and it is secreted as a heterodimer with ESAT-6, which is implicated in Mtb virulence.…”

“…1), and understanding these will inform better vaccine development. To this end, a paper from Musvosvi et al 3 in this issue of Nature Medicine sheds welcome new light on the importance of the antigen and epitope (short peptide fragments of antigens) specificity of T cells in immune control of TB. To do this, the authors prospectively collected blood samples from Mtb-infected participants who progressed to active TB (progressors) and those who did not (controllers), and carried out T cell receptor (TCR) sequencing and bioinformatic analyses informed by structural studies.…”

“…Leveraging well-characterized TB cohorts in which some individuals progressed to active TB disease and other individuals remained well, Musvosvi et al 3…”

Rare VariableM. tuberculosisAntigens induce predominant Th17 responses in human infection

“…However, in HIV, there is evidence that CD4 and CD8 T cells that recognize the env protein are associated with poorer control while T cells that recognize gag are associated with better control of viremia (Kiepiela et al 2007; Ranasinghe et al 2012). A recent report emphasized the relevance of identifying distinct Mtb antigen-specific T cell repertoires as it identified T cell antigen receptor (TCR) clonotypes that are associated with control (maintained latent TB) or progression to active TB disease (Musvosvi et al 2023).…”