GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336443/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336443GEOGSEfalseRestricted MHCII trafficking in Mycobacterium tuberculosis-infected M2-like macrophages limits CD4+ T cell activationRecognition of infected macrophages by CD4+ T cells is essential to immune protection against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). However, not all infected macrophage subsets successfully elicit T cell activation. We recently discovered that M2-like macrophages fail to efficiently activate memory CD4+ T cells when infected with Mtb, yet successfully elicit T cell activation when loaded with peptides, g-irradiated bacteria, or Mtb whole cell lysate. Since the mechanisms underlying CD4+ T-cell evasion by infected M2 but not M1-like macrophages remain underexplored, we sought to determine the genes and pathways unique to Mtb infection of M2-like cells, including alveolar macrophages. RNA sequencing of macrophage subsets infected with virulent Mtb identified enrichment of IL-10 and type I IFN signaling pathway genes, including IL10RA and HERC5, respectively, in infected M2-like and human alveolar macrophages. 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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 sapiens[42465483]