Single cell transcriptomics of the T cell response to Mycobacterium Tuberculosis reveals phenotypic diversity within and between infected individuals

Abstract Tuberculosis (TB) is an airborne infectious disease and caused by Mycobacterium Tuberculosis (MTB) and the leading infectious cause of adult mortality in the world. Despite its high transmission rate and high fatality in untreated individuals, currently there is only one widely-used vaccine and it does not protect adults from TB. The development of a more efficacious vaccine has been hampered by limitations in our understanding of the type of immunity required to protect against TB. Using single cell transcriptomics, we have developed a method of identifying Mtb-reponsive T cell clones and performing deep phenotyping on them. Our study of circulating cells in latently-infected individuals reveal robust differences in the transcriptional phenotypes of Mtb-responsive CD4 T cells, both within and between individuals. We expect that this transcriptome-wide view of Mtb-specific cells, and a simultaneous view of the inciting antigens at peptide resolution, will enable a next-generation studies of the response to Mtb in natural history and vaccine trial cohorts, with the potential to reveal correlations of protection and therefore new vaccine targets and mechanisms.