MicroRNAs maintain identity

Three recent papers published in The Journal of Experimental Medicine show that microRNAs are needed to safeguard the function of regulatory T (T_Reg) cells.

T_Reg cells are known to be essential for immune homeostasis and act by suppressing the activation of autoreactive T cells. Accordingly, the ablation of T_Reg cells or mutation of the gene that encodes the T_Reg-cell-defining transcription factor forkhead box P3 (FOXP3) results in a devastating autoimmune lymphoproliferative disease in mice. The new data further support this important function of T_Reg cells and reveal that microRNAs are required to maintain T_Reg-cell activity, which befits their suggested role in 'buffering' gene expression in conditions of environmental stress.

MicroRNAs, which regulate gene expression at the post-transcriptional level, are generated from longer RNA transcripts through sequential processing by the enzymes Drosha and Dicer; deletion of these enzymes can therefore be used to study the effects of microRNA deficiency. In all three studies, mice with a T_Reg-cell-specific deletion of Dicer developed a spontaneous, aggressive autoimmune disease that was indistinguishable from that observed in mice that lack Foxp3 or T_Reg cells. Chong et al. also found that conditional deletion of Drosha in T_Reg cells had the same devastating effect, which confirms that Drosha and Dicer function in the same pathway. The finding that mice in which Dicer (or Drosha) was deleted in all T cells suffered a less severe, delayed lymphoproliferative disease suggested that unknown defects in the activation or function of conventional T cells caused by the absence of microRNAs could mask the devastating consequences of Dicer deficiency in T_Reg cells.

T_Reg-cell-targeted microRNA deficiency did not grossly affect the thymic development, proliferation or survival of T_Reg cells, although a decrease in the frequency of FOXP3⁺ thymocytes and mature peripheral T_Reg cells (possibly a consequence of impaired peripheral homeostasis, as suggested by Liston et al.) were noted by all groups. More importantly, however, Dicer-deficient T_Reg cells showed evidence of altered differentiation and defective function in the periphery. Zhou et al. reported that Dicer-deficient T_Reg cells seemed to be more activated and expressed genes that are normally associated with effector T cells, including granzymes, interferon-γ and CD127. Similarly, Liston et al. showed that in an inflammatory setting, Dicer-deficient T_Reg cells lost their normal anergic phenotype and had impaired homeostasis. Zhou et al. observed downregulation of FOXP3 expression in a subset of Dicer-deficient T_Reg cells and altered expression of other T_Reg-cell-associated markers, such as neuropilin-1 and cytotoxic T-lymphocyte antigen 4, in most other T_Reg cells, which suggests that microRNAs are important for maintaining a stable T_Reg-cell phenotype.

Further characterization of the function of Dicer-deficient T_Reg cells by all three groups revealed a marked defect in their suppressive capacity in vitro and in vivo. Importantly, Liston et al. noted that the suppressive defect was most profound in T_Reg cells under inflammatory conditions and suggested that this could account for the rapid onset of severe disease in mice with a targeted deletion of Dicer in T_Reg cells.

So, although it is not clear which individual microRNAs are involved, these studies highlight an essential role for microRNA-dependent regulation of gene expression in the maintenance of T_Reg-cell homeostasis and suppressive function.