C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells

Abstract

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.

C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity

“…Authors proposed that as prolonged type-I IFN signaling during chronic virus infection facilitates virus persistence by inducing negative immune regulators, CLEC12A inhibition may be clinically beneficial in cases of persistent infection (116,117). Similarly, the inhibitory receptor DCIR was shown to sustain type-I IFN signaling in DCs through interaction with an unidentified endogenous ligand(s) (118). Although both of these CLRs contain an ITIM in their cytoplasmic tail, and are thought to act as negative regulators of immune cell signaling, these results suggest that ITIM can somehow activate, rather than inhibit, some signaling pathways (22,118).…”

“…Similarly, the inhibitory receptor DCIR was shown to sustain type-I IFN signaling in DCs through interaction with an unidentified endogenous ligand(s) (118). Although both of these CLRs contain an ITIM in their cytoplasmic tail, and are thought to act as negative regulators of immune cell signaling, these results suggest that ITIM can somehow activate, rather than inhibit, some signaling pathways (22,118). Whether these receptors deliver a signal on their own through the ITIM motif or require a co-receptor will need further molecular dissection.…”

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

“…The original member of this family, Clec4a2, the likely ortholog of the single CLEC4A gene in humans, encodes a lectin with a broad binding specificity for mannose and fucose [112]. Studies on knockout mice lacking Clec4a2 continue to be based upon the claim that the lectin is mainly expressed by DC [113] but the global analysis showed that it is more highly-expressed in most isolated macrophage populations. Two of the DC-associated clusters contained other members of the family, Clec4a4 and Clec4b2.…”

The many ways tissue phagocytes respond to dying cells

“…Clec4a encodes DCIR, a C-type lectin receptor and member of the dendritic cell immunoreceptor (DCIR) family that was first described as an attachment factor for human immunodeficiency virus (HIV)-1 in DC (96). DCIR has also been reported to potentiate DC cross-presentation of antigen to CD8 T cells (97) and sustain type I IFN signaling (98). Notably, a polymorphism in DCIR, SNP rs2377422, is a genetic susceptibility factor for SLE and Sjogren’s syndrome (99), two autoimmune diseases where excessive apoptosis and impaired apoptotic cell clearance contribute to disease pathogenesis (15, 100).…”

“…97 DCIR has also been reported to potentiate DC cross-presentation of antigen to CD8 T cells 98 and sustain type I IFN signaling. 99 Notably, a polymorphism in DCIR, SNP rs2377422, is a genetic susceptibility factor for SLE and Sjogren's syndrome, 100 two autoimmune diseases where excessive apoptosis and impaired apoptotic cell clearance contribute to disease pathogenesis. 15,101 Clec4b1 encodes DCAR, a different member of the DCIR family that delivers antigens to the endocytic pathway in DC and enhances antigen-specific T-cell responses.…”