NRF2 inhibition of alveolar macrophage MHC II expression during Mycobacterium tuberculosis infection

During Mycobacterium tuberculosis (Mtb) infection, infected alveolar macrophages (AMs) initially up-regulate a NRF2 regulated cell-protective program, which is detrimental to host control and impedes AM activation, including MHC II expression. MHC II is critical for CD4+ T cell activation and host immunity during Mtb infection. We hypothesized that NRF2 regulates the MHC II pathway and AM antigen presentation to T cells. We found that NRF2 inhibits MHC II, but not MHC I, specifically in AMs, following Mtb infection in vitro and in vivo. NRF2 dampens Ciita and H2-Ab1 gene expression in uninfected AMs, and MHC II inhibition by NRF2 is retained following innate stimuli and IFN{gamma} exposure. NRF2 expression in Mtb-infected AMs impedes their ability to activate ESAT6-specific CD4+ T cells. Thus, although NRF2 expression enhances cell-protective functions, it has the unexpected consequence of limiting innate-adaptive crosstalk, which can impair CD4+ T cell activation and host immunity during Mtb infection. HIGHLIGHTSO_LINRF2 inhibits MHC II on AMs, but not DCs, MDMs, or PMNs, during Mtb infection C_LIO_LINRF2 inhibits Ciita and H2-Ab1 and total MHC II protein in AMs, but not in BMDMs C_LIO_LINRF2 blockade of AM MHC II is retained following PAMP and IFN{gamma} stimulation C_LIO_LINRF2 impedes the activation of antigen-specific CD4+ T cells by Ams C_LI