Single-cell transcriptomics of blood reveals a nature killer cell subset depletion in tuberculosis

Background: Tuberculosis (TB) continues to be a critical global health problem, which killed millions of lives each year. Certain circulating cell subsets are thought to differentially modulate the host immune response towards Mycobacterium tuberculosis (Mtb) infection, but the nature and function of these subsets is unclear.Methods: We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) from healthy controls (HC), latent tuberculosis infection (LTBI) and active tuberculosis (TB).Findings: Cluster analysis based on differential gene expression revealed both known and novel markers for all main PBMC types and delineated 25 cell subsets. By comparing the scRNA-seq datasets from HC, LTBI and TB, we found that infection changes the frequency of immune-cell subsets during TB development. Specifically, we observed gradual depletion of a NK cell subset (CD3-CD7+GZMB+) from HC, to LTBI and TB. We further verified that the depletion of CD3-CD7+GZMB+ subset in TB and confirmed that changes in this subset frequency can distinguish patients with TB from LTBI and HC.Interpretation: We propose that the frequency of CD3-CD7+GZMB+ in peripheral blood could be used as a novel biomarker for distinguishing TB from LTBI and HC.