2. Academic Validation
  3. C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity

C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity

  • Nat Commun. 2023 Oct 23;14(1):6718. doi: 10.1038/s41467-023-42216-3.
Fan Li # 1 2 3,  Hui Wang # 2 3,  Yan-Qi Li 2 3,  Yebo Gu 4,  Xin-Ming Jia 5 6
Affiliations

Affiliations

  • 1 Department of Stomatology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
  • 2 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
  • 3 Key Laboratory of Pathogen-Host Interactions of the Ministry of Education of China, Tongji University, Shanghai, 200092, China.
  • 4 Department of Stomatology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China. abbyyebogu@tongji.edu.cn.
  • 5 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. jiaxm@tongji.edu.cn.
  • 6 Key Laboratory of Pathogen-Host Interactions of the Ministry of Education of China, Tongji University, Shanghai, 200092, China. jiaxm@tongji.edu.cn.
  • # Contributed equally.
PMID: 37872182 DOI: 10.1038/s41467-023-42216-3
Abstract

Dimerization of C-type Lectin Receptors (CLRs) or Toll-like receptors (TLRs) can alter their ligand binding ability, thereby modulating immune responses. However, the possibilities and roles of dimerization between CLRs and TLRs remain unclear. Here we show that C-type lectin receptor-2d (CLEC2D) forms homodimers, as well as heterodimers with TLR2. Quantitative ligand binding assays reveal that both CLEC2D homodimers and CLEC2D/TLR2 heterodimers have a higher binding ability to fungi-derived β-glucans than TLR2 homodimers. Moreover, homo- or hetero-dimeric CLEC2D mediates β-glucan-induced ubiquitination and degradation of MyD88 to inhibit the activation of transcription factor IRF5 and subsequent IL-12 production. Clec2d-deficient female mice are resistant to Infection with Candida albicans, a human Fungal pathogen, owing to the increase of IL-12 production and subsequent generation of IFN-γ-producing NK cells. Together, these data indicate that CLEC2D forms homodimers or heterodimers with TLR2, which negatively regulate Antifungal immunity through suppression of IRF5-mediated IL-12 production. These homo- and hetero-dimers of CLEC2D and TLR2 provide an example of receptor dimerization to regulate host innate immunity against microbial infections.

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