Clec2d, also known as Lectin-like transcript 1 (LLT1), is a member of the C-type lectin-like domain family 2. It plays crucial roles in the immune system, especially in immune regulation and response to various stimuli. It is involved in pathways related to antifungal immunity, cell death sensing, and tumor-immune cell interactions. Its function in these processes is of great biological importance, and genetic models like knockout (KO) mouse models can be 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. Clec2d-deficient female mice are resistant to Candida albicans infection due to increased IL-12 production and IFN-γ-producing NK cells, indicating that Clec2d negatively regulates antifungal immunity by suppressing IRF5-mediated IL-12 production [1]. In cancer, the CD161-Clec2d inhibitory receptor-ligand system is important for tumor progression and immune evasion. Systematic analysis shows that Clec2d mRNA is abundant in hematological malignancies. High-affinity CD161 monoclonal antibodies that block Clec2d binding enhance T-cell-mediated immunity against hematological malignancies in vitro and in humanized mouse models [3,4].

In conclusion, Clec2d is essential in immune-related biological processes. The use of KO mouse models has revealed its role in antifungal immunity and in cancer, where targeting the CD161-Clec2d interaction could potentially be a novel therapeutic strategy for hematological malignancies.

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. Del Fresno, Carlos, Sancho, David. . Clec2d Joins the Cell Death Sensor Ranks. In Immunity, 52, 6-8. doi:10.1016/j.immuni.2019.12.015. https://pubmed.ncbi.nlm.nih.gov/31951550/

3. Kyrysyuk, Oleksandr, Wucherpfennig, Kai W. 2022. Designing Cancer Immunotherapies That Engage T Cells and NK Cells. In Annual review of immunology, 41, 17-38. doi:10.1146/annurev-immunol-101921-044122. https://pubmed.ncbi.nlm.nih.gov/36446137/

4. 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/