Clec2d, also known as Lectin-like transcript 1 (LLT1), is a C-type lectin receptor. It plays diverse roles in immune-related processes. It is involved in dimerization with other receptors like TLR2, and this dimerization modulates immune responses. Also, it has a role in sensing cell death, and is associated with immune-evasion mechanisms in tumors through its interaction with CD161 [1-3].

In Clec2d-deficient female mice, they are resistant to Candida albicans infection due to increased IL-12 production and subsequent generation of IFN-γ-producing NK cells. This indicates that Clec2d negatively regulates antifungal immunity by suppressing IRF5-mediated IL-12 production [1]. In the context of cancer, targeting the CD161-Clec2d interaction with monoclonal antibodies enhanced T-cell-mediated immunity against hematological malignancies in humanized mouse models, and pan-cancer analysis shows that the CLEC2D/KLRB1 ratio is higher in most cancer types and increases with advancing pathological stages [2,3].

In conclusion, Clec2d is a crucial player in regulating immune responses, especially in antifungal immunity and cancer immune-evasion. The use of gene-knockout mouse models has revealed its negative regulatory role in antifungal immunity and its potential as a target for cancer immunotherapy. These findings contribute to a better understanding of the underlying mechanisms of related diseases and provide potential therapeutic strategies.

References:

1. Li, Fan, Wang, Hui, Li, Yan-Qi, Gu, Yebo, Jia, Xin-Ming. 2023. C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity. In Nature communications, 14, 6718. doi:10.1038/s41467-023-42216-3. https://pubmed.ncbi.nlm.nih.gov/37872182/

2. Alvarez Calderon, Francesca, Kang, Byong H, Kyrysyuk, Oleksandr, Wittrup, K Dane, Wucherpfennig, Kai W. . Targeting of the CD161 inhibitory receptor enhances T-cell-mediated immunity against hematological malignancies. In Blood, 143, 1124-1138. doi:10.1182/blood.2023022882. https://pubmed.ncbi.nlm.nih.gov/38153903/

3. Zhu, Yaoyao, Zhang, Huajie, Shao, Ruoyang, Lu, Peiyuan, Ma, Zhongrui. 2024. Comprehensive pan-cancer analysis of KLRB1-CLEC2D pair and identification of small molecule inhibitors to disrupt their interaction. In International immunopharmacology, 140, 112908. doi:10.1016/j.intimp.2024.112908. https://pubmed.ncbi.nlm.nih.gov/39133960/