Transcriptional profile of CD8+Vα7.2+CD161+ MAITs reveals distinct gene expression compared to CD8 memory T cells

Abstract Here, we applied a cell population transcriptomics strategy to sorted human memory CD8 T cells to define novel immune signatures of latent tuberculosis infection (LTBI) and understand the phenotype of tuberculosis (TB)-specific T cells. We found a 41-gene signature that could discriminate between memory CD8 T cells from healthy LTBI subjects and noninfected controls. The gene signature was dominated by genes known to be 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 the MAITs in more detail in these cohorts. Phenotyping based on Vα7.2 and CD161 expression and MR1 tetramers revealed 2 distinct populations of CD8+Vα7.2+CD161+ T cells: MR1 tetramer-restricted and MR1 tetramer-unrestricted, both of which had a distinct gene expression profile compared to CD8 memory T cells. Transcriptomic analysis of LTBI vs. noninfected individuals did not reveal significant differences for MR1 tetramer-restricted cells. However, interestingly, gene expression of MR1 tetramer-unrestricted cells showed a very different profile with large inter-individual diversity and a TB-specific signature. This was further strengthened by a more diverse TCR-α and -β repertoire of MR1 tetramer-unrestricted cells as compared to MR1 tetramer-restricted. Thus, cell population transcriptomics revealed a dominant MAIT signature in CD8 memory T cells that upon detailed investigation provided novel insights into the phenotype of different MAIT populations implicated in tuberculosis.