Nfatc2, the Nuclear factor of activated T cells 2, is a transcription factor crucial for the effector function of CD8+ T cells. It is involved in immune-related pathways and plays a significant role in the body's immune responses, especially in the context of infections and cancer [1].

In CD8+ T cells, Dapl1 deficiency was found to rescue NFATc2 activation, preventing functional exhaustion of these cells in chronic infection and cancer, suggesting that Dapl1 is a regulator of NFATc2 activation [1]. In lung adenocarcinoma, NFATc2 promotes lactate production and M2 macrophage polarization by transcriptionally regulating USP17 [2]. In cholangiocarcinoma, NFATc2 promotes cancer progression via the NEDD4/FBP1 axis [3]. Genetic inhibition of Nfatc2 in mice attenuated asparaginase hypersensitivity, as NFATC2-deficient mice had reduced anti-ASNase antibodies and less severe shock responses [4]. Also, macrophage-specific activation of NFATC2 was identified as essential to trehalose 6,6'-dimycolate-mediated angiogenesis during mycobacterial infection [5].

In conclusion, Nfatc2 is essential for CD8+ T cell effector function and is involved in multiple disease-related processes such as cancer progression, hypersensitivity reactions, and angiogenesis during mycobacterial infection. Studies using gene-knockout mouse models have been instrumental in revealing these functions, providing insights into potential therapeutic targets for various diseases.

References:

1. Zhu, Lele, Zhou, Xiaofei, Gu, Meidi, Cheng, Xuhong, Sun, Shao-Cong. 2022. Dapl1 controls NFATc2 activation to regulate CD8+ T cell exhaustion and responses in chronic infection and cancer. In Nature cell biology, 24, 1165-1176. doi:10.1038/s41556-022-00942-8. https://pubmed.ncbi.nlm.nih.gov/35773432/

2. Wang, Liang, Ma, Yuanyuan, Zhang, Shanyuan, Yang, Yue, Huang, Bo. 2024. NFATc2 promotes lactate and M2 macrophage polarization through USP17 in lung adenocarcinoma. In Anti-cancer drugs, 35, 385-396. doi:10.1097/CAD.0000000000001582. https://pubmed.ncbi.nlm.nih.gov/38386130/

3. Zhao, Wei, Zhao, Jing, Li, Kun, Tan, Bin, Shi, Jian. 2023. Oncogenic Role of the NFATC2/NEDD4/FBP1 Axis in Cholangiocarcinoma. In Laboratory investigation; a journal of technical methods and pathology, 103, 100193. doi:10.1016/j.labinv.2023.100193. https://pubmed.ncbi.nlm.nih.gov/37285922/

4. Rathod, Sanjay, Ramsey, Manda, Finkelman, Fred D, Fernandez, Christian A. . Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice. In Blood advances, 4, 4406-4416. doi:10.1182/bloodadvances.2020002478. https://pubmed.ncbi.nlm.nih.gov/32931581/

5. Brewer, W Jared, Xet-Mull, Ana María, Yu, Anne, Walton, Eric M, Tobin, David M. . Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection. In Cell reports, 41, 111817. doi:10.1016/j.celrep.2022.111817. https://pubmed.ncbi.nlm.nih.gov/36516756/