Clec2d, also known as Lectin-like transcript 1 (LLT1), is a C-type lectin receptor that plays significant roles in immune regulation and cell-death sensing. It is involved in pathways related to antifungal immunity, inflammation, and tumor immune evasion. Genetic models, such as gene-knockout (KO) mouse models, are valuable for studying its functions [1,2,3].

In antifungal immunity, Clec2d forms homodimers and heterodimers with TLR2. These dimers have a higher binding ability to fungi-derived β-glucans than TLR2 homodimers. Homo-or hetero-dimeric Clec2d mediates β-glucan-induced ubiquitination and degradation of MyD88, inhibiting the activation of transcription factor IRF5 and subsequent IL-12 production. Clec2d-deficient female mice are resistant to Candida albicans infection due to increased IL-12 production and IFN-γ-producing NK cells [1]. In cancer, the interaction between the inhibitory receptor CD161 (encoded by KLRB1) and its ligand Clec2d is crucial for tumor progression and immune evasion. The CLEC2D/KLRB1 ratio is higher in most cancer types compared to normal tissues and increases with advancing pathological stages. Targeting CD161 with monoclonal antibodies enhances T-cell-mediated immunity against hematological malignancies [3,4,5].

In conclusion, Clec2d is important in regulating antifungal immunity by negatively influencing IRF5-mediated IL-12 production. In the context of cancer, the CD161-Clec2d interaction impacts tumor immune evasion. Studies using KO mouse models have been instrumental in uncovering these roles, providing insights into potential therapeutic strategies for fungal infections and cancer.