Clec9a, also known as DNGR-1, is a C-type lectin receptor family 9 member. It is exclusively expressed on type 1 conventional dendritic cells (cDC1s) and plays a pivotal role in antigen cross-presentation, modulating immune responses. It is involved in enhancing cytotoxic T lymphocyte (CTL) responses, and is associated with pathways related to anti-viral and anti-tumor immunity, as well as immune responses in infectious diseases like tuberculosis [2,4,5,6].

In cancer, downregulated Clec9A is associated with lung adenocarcinoma prognosis and the tumor immune microenvironment, and its expression affects the proliferation, apoptosis, cell cycle, and invasion of lung adenocarcinoma cells [3]. In chronic obstructive pulmonary disease (COPD), increased Clec9A expression on cDC1s is associated with cytotoxic CD8+ T cell response, suggesting its participation in CD8+ T cell-mediated chronic airway inflammation [1]. In tuberculosis, Clec9A modulates macrophage-mediated neutrophil recruitment in response to heat-killed Mycobacterium tuberculosis H37Ra by activating SYK and MAPK signaling, promoting production of CXCL8 and IL-1β [6].

In conclusion, Clec9a is crucial for antigen cross-presentation and immune response modulation. Its study in models has revealed its significance in diseases such as cancer, COPD, and tuberculosis, highlighting its potential as a biomarker and therapeutic target in these disease areas.

References:

1. Yan, Li, Wu, Xiaojie, Wu, Ping, Huang, Wei, Cui, Tianpen. 2022. Increased expression of Clec9A on cDC1s associated with cytotoxic CD8+ T cell response in COPD. In Clinical immunology (Orlando, Fla.), 242, 109082. doi:10.1016/j.clim.2022.109082. https://pubmed.ncbi.nlm.nih.gov/35901921/

2. van der Aa, Evelyn, van Montfoort, Nadine, Woltman, Andrea M. 2014. BDCA3(+)CLEC9A(+) human dendritic cell function and development. In Seminars in cell & developmental biology, 41, 39-48. doi:10.1016/j.semcdb.2014.05.016. https://pubmed.ncbi.nlm.nih.gov/24910448/

3. Miao, Fang, Lou, Zhiguo, Ji, Shuhua, Liu, Huan, Yang, Chenggang. 2021. Downregulated Expression of CLEC9A as Novel Biomarkers for Lung Adenocarcinoma. In Frontiers in oncology, 11, 682814. doi:10.3389/fonc.2021.682814. https://pubmed.ncbi.nlm.nih.gov/34616670/

4. Hussain, Zubair, Zhang, Yueteng, Qiu, Lu, Gou, Shanshan, Liu, Kangdong. 2025. Exploring Clec9a in dendritic cell-based tumor immunotherapy for molecular insights and therapeutic potentials. In NPJ vaccines, 10, 27. doi:10.1038/s41541-025-01084-2. https://pubmed.ncbi.nlm.nih.gov/39920156/

5. Lahoud, M H, Radford, K J. 2021. Enhancing the immunogenicity of cancer vaccines by harnessing CLEC9A. In Human vaccines & immunotherapeutics, 18, 1873056. doi:10.1080/21645515.2021.1873056. https://pubmed.ncbi.nlm.nih.gov/33625943/

6. Cheng, An-Chieh, Yang, Kuang-Yao, Chen, Nien-Jung, Hsieh, Shie-Liang, Tseng, Ping-Hui. 2017. CLEC9A modulates macrophage-mediated neutrophil recruitment in response to heat-killed Mycobacterium tuberculosis H37Ra. In PloS one, 12, e0186780. doi:10.1371/journal.pone.0186780. https://pubmed.ncbi.nlm.nih.gov/29065139/