Molle, A. | bioRxiv Science

bioRxiv2025

PU.1 Shapes Host Epigenetic Responses to Mycobacterium tuberculosis and Represents a Target for Host Directed Therapy

Mycobacterium tuberculosis (Mtb) infection induces widespread epigenetic changes in monocytes and macrophages. To characterize the critical factor responsible for Mtb-induced epigenetic responses, we performed an integrative analyses of chromatin modification (H3K27ac), transcription factor binding, and gene expression in human monocytes and macrophages. Our data identified PU.1 (SPI1) as a key transcriptional regulator to be upregulated and bound to gene promoters in response to Mtb. PU.1 enrichment was associated with enhanced proinflammatory and anti-apoptotic gene programs. PU.1 expression was also elevated in the lung tissues from Mtb-infected macaques and tuberculosis patients. PU.1 knockdown enhanced human macrophage apoptosis, dampened inflammation and reduced bacterial survival, suggesting its functional role in supporting Mtb infection. Pharmacological inhibition of PU.1 replicated the effects of knockdown, restricting Mtb growth without cytotoxicity. These findings identify PU.1 as a central node in the host epigenetic response to Mtb and a candidate for host-directed therapeutic targeting in tuberculosis.

immunology↗

bioRxiv2019

Dendritic cells require TMEM176A/B ion channels for optimal MHC II antigen presentation to naive CD4+ T cells

Intracellular ion fluxes emerge as critical actors of immunoregulation but still remain poorly explored. Here we investigated the role of the redundant cation channels TMEM176A and TMEM176B (TMEM176A/B) in ROR{gamma}t+ cells and conventional dendritic cells (cDCs) using germline and conditional double knock-out (DKO) mice. While Tmem176a/b appeared surprisingly dispensable for the protective function of Th17 and group 3 innate lymphoid cells (ILC3s) in the intestinal mucosa, we found that they were required in cDCs for optimal antigen processing and presentation to CD4+ T cells. Using a real-time imaging method, we show that TMEM176A/B accumulate in dynamic post-Golgi vesicles preferentially linked to the late endolysosomal system and strongly colocalize with HLA-DM. Together, our results suggest that TMEM176A/B ion channels play a direct role in the MHC II compartment (MIIC) of DCs for the fine regulation of antigen presentation and naive CD4+ T cell priming.

immunology↗