Clec4a4, also known as DCIR2 (Dendritic cell immunoreceptor 2), is a C-type lectin receptor. It is mainly expressed by CD8α -DCs and eosinophils in the small intestine, and can modulate T cell immunity and inflammation [1,3,4]. It functions as a regulatory receptor for the activation of CD8α -cDCs, and may be involved in pathways related to immunity and disease development [3]. Genetic models like KO mouse models are valuable for studying its functions.

In atherosclerosis, Clec4a4 deficiency in Ldlr-/-mice led to reduced atherosclerotic plaque formation, along with altered lipid metabolism and myeloid immune cell distribution, suggesting a pro -atherosclerotic role of Clec4a4 [1]. In antitumor immunity, mClec4A4 deficiency in tumor -bearing mice reduced tumor development, enhanced antitumor immune responses, and improved the immunosuppressive tumor microenvironment, indicating it acts as a negative immune checkpoint regulator [2]. Also, Clec4a4-/-CD8α -cDCs showed enhanced cytokine production and T -cell priming, and Clec4a4-/-mice had TLR -mediated hyperinflammation, augmented T -cell responses upon antigenic immunization, and resistance to microbial infection [3].

In conclusion, Clec4a4 is a regulatory receptor that plays important roles in modulating immune responses and inflammation. KO mouse models have revealed its significance in diseases such as atherosclerosis and cancer. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential targets for treatment [1,2,3].

References:

1. Bellini, Rossella, Moregola, Annalisa, Nour, Jasmine, Bonacina, Fabrizia, Norata, Giuseppe Danilo. 2022. Dendritic cell marker Clec4a4 deficiency limits atherosclerosis progression. In Atherosclerosis plus, 51, 8-12. doi:10.1016/j.athplu.2022.12.001. https://pubmed.ncbi.nlm.nih.gov/36969702/

2. Uto, Tomofumi, Fukaya, Tomohiro, Mitoma, Shuya, Hishikawa, Yoshitaka, Sato, Katsuaki. . Clec4A4 Acts as a Negative Immune Checkpoint Regulator to Suppress Antitumor Immunity. In Cancer immunology research, 11, 1266-1279. doi:10.1158/2326-6066.CIR-22-0536. https://pubmed.ncbi.nlm.nih.gov/37432112/

3. Uto, Tomofumi, Fukaya, Tomohiro, Takagi, Hideaki, Malissen, Bernard, Sato, Katsuaki. 2016. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity. In Nature communications, 7, 11273. doi:10.1038/ncomms11273. https://pubmed.ncbi.nlm.nih.gov/27068492/

4. Wang, Wei-Le, Kasamatsu, Jun, Joshita, Satoru, Cella, Marina, Colonna, Marco. 2022. The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4+ eosinophils unique to the small intestine. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2204557119. doi:10.1073/pnas.2204557119. https://pubmed.ncbi.nlm.nih.gov/35653568/