C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells
Significance Tuberculosis (TB) is an immunopathology, mostly of the lung, due to an overexuberant immune response to the bacterial pathogen Mycobacterium tuberculosis . Here, we demonstrate in vitro and in vivo that dendritic cell (DC) immunoreceptor (DCIR), a C-type lectin receptor expressed by DCs, modulates immunity to TB by sustaining type I IFN signaling in DCs. These findings were generalized beyond TB, in a model of in vivo antigen-presentation assay unrelated to M. tuberculosis , suggesting that they may extend to other pathologies, such as viral infections or autoimmune disorders. Thus, modulating DCIR activity may help to develop type I IFN-targeting therapies for a large repertoire of inflammatory disorders, including TB. Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis -infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen’s control through sustaining type I IFN signaling in DCs.
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