Another roll of the Dice(r)

New findings in The Journal of Experimental Medicine show that naturally occurring CD4⁺CD25⁺ regulatory T (T_Reg) cells and conventional CD4⁺ (CD25⁻) T cells have distinct microRNA (miRNA) profiles, and that the ribonuclease III enzyme Dicer, which is required for embryonic development, is involved in the development of T_Reg cells.

Mature miRNAs are short (21–22 nucleotides), single-stranded RNAs that are generated from longer precursors by Dicer. miRNAs regulate gene expression at the post-transcriptional level by targeting matching pieces of messenger RNA for degradation, thereby decreasing the production of the corresponding protein, and they have been proposed to have a role in haematopoiesis. In their study of T_Reg-cell biology, Cobb et al. analysed miRNA expression in both T_Reg cells and conventional CD4⁺ T cells in mice. These two cell populations had distinctly different expression profiles, with 68 miRNAs being differentially expressed between T_Reg cells and CD4⁺ T cells. Interestingly, on activation, CD4⁺ T cells transiently adopted a profile of miRNA expression that was similar to that of T_Reg cells. Forced expression of the transcription factor forkhead box P3 (FOXP3), a major marker and regulator of the development and function of mouse T_Reg cells, in CD4⁺ T cells showed that 9 of the 10 miRNAs that were upregulated in FOXP3-expressing cells were among the top 20 miRNAs preferentially expressed in T_Reg cells. Therefore, either directly or indirectly, FOXP3 was contributing to the T_Reg-cell miRNA expression profile.

Deletion of Dicer from the T-cell lineage resulted in the absence of miRNA expression, reduced numbers of T_Reg cells and the development of immune pathology in the colon, lung and liver of a proportion of the mice examined. But is Dicer involved in T_Reg-cell differentiation, or in T_Reg-cell maintenance or homeostasis? Further investigation focused on the first wave of T_Reg-cell development in the thymus and revealed that thymic differentiation of Dicer-deficient (and therefore also mature miRNA-deficient) T_Reg cells was impaired. The induction of FOXP3 in peripheral naive CD4⁺ T cells by transforming growth factor-β (TGFβ) was also compromised in the absence of Dicer.

In a cell-autonomous manner, therefore, Dicer is required to maintain normal numbers of T_Reg cells in peripheral lymphoid organs, for T_Reg-cell development in the thymus and for the efficient induction of FOXP3 expression by TGFβ in CD4⁺ T cells. These findings indicate a novel role for Dicer in immune regulation.