UC San Diego

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the transcriptome by degrading or suppressing the translation of target mRNAs. Loss of the microRNA network in regulatory T-cells (Tregs) leads to the development of systemic autoimmunity and inflammation due to loss of immunological control. Previously our lab discovered critical roles of the miR-23-27-24 (miR-23) family in controlling the differentiation and function of follicular helper and effector T-cells. To explore the functions of the entire miR-23 family in Tregs, we utilized a transplantable tumor model. We found that loss of the miR-23 family in Tregs impeded tumor growth and reduced Treg frequency. However, there was no apparent increase in the effector functions of antitumor CD8+ T-cells because miR-23 deficient Tregs were more suppressive, compensating for reduced intratumoral Tregs. This increase in suppression is potentially attributed to an increase in IL-10, a target of miR-27. Further profiling of the immune cell landscape found an increase in Natural Killer (NK) cells, which have been shown to be activated by IL-10. The transcription factor TCF1, a target of miR-24, was found to be increased in miR-23 family deficient intratumoral Tregs, leading to a loss of TCF1- effector Tregs. RNA-sequencing found that loss of the miR-23 family in intratumoral Tregs led to a reduction in IL2-STAT5 signaling. Collectively, our work demonstrates that loss of the miR-23 family in Tregs leads to enhanced suppression, potentially due to increased IL-10, loss of TCF1- Tregs, and impaired proliferative capacity.