Quantitative and Qualitative Perturbations of CD8⁺ MAITs in Healthy Mycobacterium tuberculosis–Infected Individuals

CD8 T cells are considered important contributors to the immune response against Mycobacterium tuberculosis, yet limited information is currently known regarding their specific immune signature and phenotype. In this study, we applied a cell population transcriptomics strategy to define immune signatures of human latent tuberculosis infection (LTBI) in memory CD8 T cells. We found a 41-gene signature that discriminates between memory CD8 T cells from healthy LTBI subjects and uninfected controls. The gene signature was dominated by genes associated with mucosal-associated invariant T cells (MAITs) and reflected the lower frequency of MAITs observed in individuals with LTBI. There was no evidence for a conventional CD8 T cell–specific signature between the two cohorts. We, therefore, investigated MAITs in more detail based on Vα7.2 and CD161 expression and staining with an MHC-related protein 1 (MR1) tetramer. This revealed two distinct populations of CD8⁺Va7.2⁺CD161⁺ MAITs: MR1 tetramer⁺ and MR1 tetramer^-, which both had distinct gene expression compared with memory CD8 T cells. Transcriptomic analysis of LTBI versus noninfected individuals did not reveal significant differences for MR1 tetramer⁺ MAITs. However, gene expression of MR1 tetramer^- MAITs showed large interindividual diversity and a tuberculosis-specific signature. This was further strengthened by a more diverse TCR-α and -b repertoire of MR1 tetramer^- cells as compared with MR1 tetramer⁺. Thus, circulating memory CD8 T cells in subjects with latent tuberculosis have a reduced number of conventional MR1 tetramer⁺ MAITs as well as a difference in phenotype in the rare population of MR1 tetramer^- MAITs compared with uninfected controls.