Highlight of 2023: big impacts of microRNAs in T cells

In 2023, several significant discoveries on the function of microRNAs in the immune system were reported. Here we discuss several notable papers that revealed important functions in T cells. In 2023, several significant discoveries on the function of microRNAs in the immune system were reported. Here we discuss several notable papers that revealed important functions in T cells. MicroRNAs are small (~22 nt) noncoding RNAs that play a crucial role in post-transcriptional gene regulation by inhibiting protein translation of target messenger RNA and triggering messenger RNA degradation.1 The impacts of microRNAs on cellular biology are extensive, regulating diverse cellular processes including differentiation, proliferation and effector functions. Abnormalities in microRNA pathways are increasingly associated with various diseases, including those involving the immune system.2 The complex and indispensable roles of microRNAs in immune cells continue to be a focus of investigation by the field. In 2023, several significant discoveries on the regulatory mechanisms of microRNAs in immunity were reported, particularly in T cells. Notable were reports on miR-150, miR-15/16 and miR-155, and how they regulate T-cell biology in the context of disease, such as experimental autoimmune encephalomyelitis (EAE) and melanoma (Figure 1).3-7 miR-150 and the miR-15/16 microRNA clusters were identified as regulators of T-cell survival and expansion. Ménoret et al.3 reported that miR-150 plays a role in promoting the apoptosis of antigen-specific conventional CD4+ T cells after staphylococcal enterotoxin A immunization (Figure 1a). RNA-sequencing analysis suggests that miR-150 may exert its effects in these T cells via the mitochondria by downregulating the expression of genes associated with superoxide levels and apoptosis.3 However, the precise targets of miR-150 were not defined. In regulatory T cells (Tregs), it appears that miR-15/16 microRNAs are responsible for controlling their expansion and survival. These microRNAs are encoded by the miR-15a/16–1 and miR-15b/16–2 genes. Johansson et al.4 reported that the two miR-15/16 genes restrict the proliferation of Tregs (Figure 1d). Interestingly, this was specific to thymic-derived Tregs, while peripheral-induced Tregs remained unaffected. A significant consequence of miR-15/16 deficiency was the accumulation of CD25lo Tregs. While low CD25 expression might be expected to result in a loss of interleukin (IL)-2–dependent survival signals, this appeared to be offset by the upregulation of CD127. Thus, different microRNAs regulate the proliferation and survival of distinct T-cell subsets and could potentially represent novel therapeutic opportunities. Aside from a role in T-cell proliferation and survival, the miR-15/16 cluster also regulates Treg cell differentiation and function.4, 5 Dong et al.5 reported that the deletion of the miR-15/16 genes in Tregs led to a specific gain of Tregs displaying an effector phenotype along with increased suppressive activity (Figure 1e). They showed that miR-15/16 controls Treg cell differentiation and function by targeting the transcription factor interferon regulatory factor 4 (IRF4), and the IRF4-dependent molecule neuritin. However, Johansson et al.4 argued in their paper that as a population, miR-15/16–deficient Tregs exert similar suppressive capacity as control Tregs. On a per-cell basis, they found that miR-15/16–deficient Tregs were less suppressive, while their greater proliferation compensated for this impaired suppressive capacity (Figure 1d). It is important to note the different mouse models used in the two studies, with Dong et al.5 using Treg-specific Foxp3-Cre deletion and Johansson et al.4 using pan-T–cell CD4-Cre deletion. Differences between the two studies could potentially be a result of the influence of miR-15/16 via other T cells, and thus the impact on Treg functions may be context dependent, which requires further investigation. Moreover, miR-15/16 microRNAs and another microRNA, miR-155, were reported to be important regulators of T-cell function in the context of multiple sclerosis and melanoma. In EAE, the mouse model of multiple sclerosis, Tregs are essential for reducing the severity of inflammation and facilitating recovery from disease by suppressing autoreactive T cells.8 Dong et al.5 reported that mice with Treg-specific deficiency of the miR-15/16 genes exhibit attenuated immune responses and a milder disease following the induction of EAE (Figure 1e). Staying with EAE, Thompson et al.6 reported that mice with T-cell– or dendritic cell–specific miR-155 deficiency exhibit significantly reduced disease severity (Figure 1b). Specifically, the CD4-Cre deletion of miR-155 resulted in decreased frequencies of T helper 1 and T helper 17 cells in the brain, along with a reduction of activated T cells in the spinal cord. These findings demonstrate the importance of different microRNAs in different immune cell types, especially in the context of disease processes, such as EAE. Therefore, therapeutic approaches aimed at inhibiting specific microRNAs represent potential strategies for attenuating EAE and other autoimmune or inflammatory diseases. Furthermore, both miR-15/16 and miR-155 microRNAs have significant roles in anti-tumor immunity.4, 7 According to Vaddi et al.,7 cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression by Treg cells is significantly reduced or nearly absent in patients with metastatic melanoma, with the inhibition of CTLA-4 messenger RNA expression attributed to the increased miR-155 in the cells (Figure 1c). Low CTLA-4 expression in both tumors and blood is linked to poorer overall survival in patients with metastatic melanoma. Given that downregulation of CTLA-4 expression is observed in patients with nonresponsive melanoma undergoing anti–programmed cell death protein-1 (anti–PD-1) immunotherapy, targeting miR-155 to relieve the repression of CTLA-4 may represent a potential strategy to enhance the effectiveness of immunotherapy in melanoma. In addition, Johansson et al.4 suggested that the selective deletion of the miR-15/16 genes in Tregs might be advantageous in cancer immunotherapies. As these microRNAs are required to maintain robust CD25 expression on Tregs regardless of IL-2 availability, it can be inferred that inhibiting miR-15/16 microRNAs in Tregs may limit their IL-2 sensitivity and suppress the IL-2–induced Treg expansion that can interfere with antitumor immune responses. Meanwhile, it would still preserve the IL-2 responses of other tumor-infiltrating immune cells. Taken together, these five studies provide novel insights and robust evidence for the essential and intricate roles of miR150, miR-15/16 and miR-155 in T cells. These findings also suggest that further elucidation of how microRNAs regulate T-cell biology could potentially yield novel treatment options for multiple sclerosis and melanoma. Moreover, this may lead to the development of promising therapeutic approaches targeting specific microRNAs for other diseases. We look forward to continued research on this topic in the future. The authors have no conflicts of interest to declare. Yangnan Zhang: Conceptualization; writing – original draft; writing – review and editing. Mark MW Chong: Conceptualization; writing – original draft; writing – review and editing.