Rorc, also known as retinoic acid receptor-related orphan receptor gamma, is a key DNA-binding transcription factor. It is responsible for the differentiation of T helper 17 (Th17) cells and plays a role in lymphoid organogenesis, thymopoiesis, and lymph node organogenesis. It is also involved in pathways related to mucosal immunity, autoimmunity, and cancer, and is associated with the development of the lymphatic system [4].

In IKKβ(EE)Hep mice crossed with RORc knockout mice, RORc-expressing cells were found to negatively regulate tertiary lymphoid structure (TLS) formation in the context of inflammation-associated liver cancer. In the absence of these cells, TLSs increased in number and acquired anti-tumorigenic properties [2]. In Th17 cells, although RORα (co-expressed with RORγt in Th17 cells) is dispensable for Th17 cell differentiation, it is necessary for optimal Th17 responses in peripheral tissues. Cooperative binding of RORα and RORγt to a Rorc cis-regulatory element is essential for Th17 lineage maintenance in vivo [1]. Also, Notch signaling promotes upregulation of RORC, enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions in multi-potent and uni-potent innate lymphoid cell precursors, and interfering with RORC compromises ILC3 effector functions and suppresses ILC production [3].

In conclusion, Rorc is crucial for the differentiation of Th17 cells and has a significant impact on various biological processes such as lymphoid organogenesis, mucosal immunity, and cancer-related immune responses. Gene knockout mouse models have been instrumental in revealing its role in Th17 cell-related functions, lymphatic system development, and the regulation of TLS formation in liver cancer, providing valuable insights into potential therapeutic targets for autoimmune diseases, cancer, and lymphatic disorders.

References:

1. Hall, Jason A, Pokrovskii, Maria, Kroehling, Lina, Lee, June-Yong, Littman, Dan R. 2022. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. In Immunity, 55, 2027-2043.e9. doi:10.1016/j.immuni.2022.09.013. https://pubmed.ncbi.nlm.nih.gov/36243007/

2. Cinnamon, Einat, Stein, Ilan, Zino, Elvira, Parnas, Oren, Pikarsky, Eli. 2024. RORc-expressing immune cells negatively regulate tertiary lymphoid structure formation and support their pro-tumorigenic functions. In Journal of hepatology, , . doi:10.1016/j.jhep.2024.12.015. https://pubmed.ncbi.nlm.nih.gov/39710149/

3. Croft, Carys A, Thaller, Anna, Marie, Solenne, Casanova, Jean-Laurent, Di Santo, James P. 2022. Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation. In Nature communications, 13, 4344. doi:10.1038/s41467-022-32089-3. https://pubmed.ncbi.nlm.nih.gov/35896601/

4. Michelini, Sandro, Ricci, Maurizio, Serrani, Roberta, Dundar, Munis, Bertelli, Matteo. 2020. Possible Role of the RORC Gene in Primary and Secondary Lymphedema: Review of the Literature and Genetic Study of Two Rare Causative Variants. In Lymphatic research and biology, 19, 129-133. doi:10.1089/lrb.2020.0030. https://pubmed.ncbi.nlm.nih.gov/32960152/