Role of miRNAs in regulatory T cell-mediated immunological tolerance

Abstract

Regulatory T (Treg) cells play an important role in maintaining immune homeostasis and the balance between immunity and tolerance. Expression of Foxp3 is essential for the differentiation and function of Treg cells as ablation or mutation of this transcription factor results in the development of severe autoimmune diseases in mice and in humans. Recent studies demonstrated that microRNAs (miRNAs) are also critical for Treg cell homeostasis and suppressor function. Mice knocked out for Dicer or Drosha (two enzymes essential for miRNA biogenesis) in Foxp3+ cells harbor impaired Treg cell populations, which leads to a fatal systemic autoimmune disease similar to that was observed in mice without Treg cells. Among the miRNAs that are differentially expressed in Treg cells, the family of miR-23-27-24 is of particular interest. While their role in immune regulation remains not well established, recently it was shown that mice with T cell-specific miR-23 cluster ablation developed Th2-associated immunopathology during airway allergic reaction. On the other hand, the role of this cluster in regulating Treg cells has not been demonstrated yet. In this application, we hypothesize that the absence of this miRNA family in Treg cells will impact their suppressor function leading to unbalanced immune responses. By using the loss-of-function genetic approaches, we will directly assess the role of miR-23 clusters in controlling Treg cell biology.