Restricted MHCII trafficking in Mycobacterium tuberculosis-infected M2-like macrophages limits CD4+ T cell activation

However, genes involved in MHC II trafficking, such as AP1M2, were higher in infected M1-like macrophages. In complementary experiments using fluorescent microscopy and flow cytometry, we observed impaired trafficking of newly synthesized MHC II to the plasma membrane of Mtb-infected M2-like macrophages despite high total surface MHC II levels. Neutralization of IL-10 or knockdown of HERC5 restored MHC II trafficking to the cell surface among infected M2-like macrophages and significantly enhanced activation of memory CD4+ T cells in an MHC II-dependent manner.

These findings identify coordinated IL-10 and type I IFN signaling as key mechanisms that restrict MHC II trafficking to the plasma membrane in Mtb-infected M2-like macrophages, thereby limiting antigen presentation and CD4+ T cell activation. We propose that host-directed therapies targeting these pathways in infected alveolar macrophages will facilitate T cell recognition for the prevention or treatment of active TB.