Diminished IFN-γ responses and epigenetic dysregulation in post-tuberculosis immune profiles 4006

Abstract Description TB is a prototypical chronic infection in humans with previous studies demonstrating long-lasting epigenetic scars. The current study explores the long-term impact of epigenetic perturbations on T cell functionality. Flow analysis demonstrates TB survivors have reduced antigen induced IFN-γ responses. Single nuclei sequencing identifies a lymphocyte subcluster that enriches for immune checkpoint genes, found 6-fold higher among TB patients compared to healthy controls. Notably, in cured TB patients, IFN-γ production appears restricted to terminally exhausted T cells, without contribution from activated or progenitor-exhausted cells. UMAP clustering demonstrates a common exhausted transcriptional signature among CD4, CD8, and NK lymphocytes. Sc-ATAC further demonstrates progenitor and terminal exhausted lymphocyte subsets with the exhausted cluster enriching for chromatin accessibility at IKZF2, TOX, BATF3, PDCD1, CTLA4, IRF4, ENTPD1, TET2, DNMT3A, METTL6, EZH2. These findings demonstrate an increase in epigenetic exhausted lymphocytes, with a common signature between CD4, CD8, and NK lymphocytes that remains increased after successful TB treatment. Topic Categories Immune Mechanisms of Human Disease (HUM)