Fig. 1

Schematic diagram of the cooperation between phagocytes/dendritic cells and T/NK cells during mycobacterial infection. Proteins for which mutations in the corresponding genes have been associated with MSMD are indicated in red. Following phagocytosis of mycobacteria, pattern recognition receptors (PRRs) activate and induce the production and release of IL-12, IL-23, and ISG15. These cytokines bind to their receptors (IL-12R, IL-23R, and LFA-1) on T-helper and NK cells, inducing the production of IFN-γ via TYK2/JAK2-dependent pathways, using STAT4 and STAT3 dimers, as well as the transcription factors RORC and T-bet. In turn, secreted IFN-γ binds to its receptor (IFNγR) on the surface of macrophages and dendritic cells leading to the activation of JAK1/JAK2-dependent pathway involving STAT1, IRF8, and IRF1 transcription factors, which enhances the production of IL-12, IL-23, and ISG15 and promotes expression of interferon-stimulated genes (ISGs). USP18 liberates ISG15 from other bound proteins and ISG15 protects USP18 from degradation. Besides, the interaction of CD40 with its ligand leads to the activation of NEMO, which activates and releases the NF-kB transcription factors. This enhances the ability of phagocytes to eliminate intracellular microorganisms