An essential role for miR-15/16 in Treg suppression and restriction of proliferation

Abstract

The miR-15/16 family targets a large network of genes in Tcells to restrict their cell cycle, memory formation, and survival. Upon Tcell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector Tcells to mediate a sustained response. Here, we used conditional deletion of miR-15/16 in regulatory Tcells (Tregs) to identify immune functions of the miR-15/16 family in Tcells. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16 deficiency alters expression of critical Treg proteins and results in accumulation of functionally impaired FOXP3loCD25loCD127hi Tregs. Excessive proliferation in the absence of miR-15/16 shifts Treg fate and produces an effector Treg phenotype. These Tregs fail to control immune activation, leading to spontaneous multi-organ inflammation and increased allergic inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance.