TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response

• Published in: Nature communications 2020-04, Vol.11 (1), p.1913-1913, Article 1913
• Main Authors: Chen, Jianwen, He, Ruirui, Sun, Wanwei, Gao, Ru, Peng, Qianwen, Zhu, Liwen, Du, Yanyun, Ma, Xiaojian, Guo, Xiaoli, Zhang, Huazhi, Tan, Chengcheng, Wang, Junhan, Zhang, Wei, Weng, Xiufang, Man, Jianghong, Bauer, Hermann, Wang, Qing K., Martin, Bradley N., Zhang, Cun-Jin, Li, Xiaoxia, Wang, Chenhui
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 14/19; 38/61; 631/250/249/1313/1666; 631/250/2499; 631/250/255/1672; 631/250/262/2106; 631/250/516; 64/60; 82/58; 82/80; 96/95; Animal models; Animals; Antifungal agents; Antifungal Agents - immunology; Antifungal Agents - pharmacology; Autoimmune diseases; Candidemia; Candidiasis - immunology; CARD Signaling Adaptor Proteins - metabolism; Cell Differentiation; Cytokines; Cytokines - metabolism; Differentiation (biology); Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - microbiology; Experimental allergic encephalomyelitis; Female; Fungi; Fungicides; GTPase-Activating Proteins - chemistry; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Helper cells; Humanities and Social Sciences; Humans; Immune response (cell-mediated); Infectious diseases; Inflammation; Lectins, C-Type - metabolism; Lymphocytes; Lymphocytes T; Male; Mice, Knockout; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - complications; Multiple Sclerosis - immunology; Myeloid cells; Phosphorylation; Receptor, EphB2 - immunology; Receptor, EphB2 - metabolism; Receptors, Immunologic; Receptors, Pattern Recognition - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signaling; Th17 Cells - immunology; Th17 Cells - metabolism; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15564-7

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity. TAGAP gene variants are linked to human autoimmunity. Here the authors identify TAGAP as a Dectin-1 and EphB2-binding protein mediating antifungal innate immune signaling and cytokine production, and demonstrate TAGAP in non-T cells promotes Th17 response in mouse models of infection and autoimmunity.