Abstract
Foxp3+ regulatory T cells (Treg) are the central regulators of immunity and tolerance. Defects in Treg generation
and/or functions lead to lethal systemic autoimmune inflammation in both mice and human, demanding a tight
regulation of Treg homeostasis. Determining factors capable of modulating Treg function is thus a subject of
utmost importance. Among the factors is microRNA, a small non-coding RNA molecule known to regulate gene
expression. There is plethora of evidence that miRNAs play a critical role in Treg generation and functions.
However, our understanding the mechanisms by which Treg-derived miRNA modulates Treg functions is
relatively limited. Glucocorticoids are the frontline treatment option for many inflammatory diseases, including
autoimmunity and allergy. Despite the broad use, the precise immune suppressive mechanisms used by
glucocorticoids remain largely elusive. We recently reported that Tregs are indispensable during glucocorticoid-
induced treatment of chronic inflammation. Mechanistically, we uncovered that a novel miR-342 is induced by
glucocorticoid stimulation in Tregs and that miR-342 targets metabolic regulator, Rictor, to control Treg metabolic
programming. From the preliminary studies we also found that miR-342 is highly expressed in Tregs and that it
is further enhanced by dexamethasone (Dex) stimulation. Interestingly, miR-342 expression in Tregs appears to
be critical for Treg suppressive function. Moreover, miR-342 was also detected in the serum following Dex
treatment. To our surprise, Dex-induced serum miR-342 was detected in steroid-sensitive but not in steroid-
resistant inflammation. Based on the compelling evidence, we propose the hypothesis that miR-342 is a
glucocorticoid-induced miRNA in Tregs that plays a regulatory role in Tregs’ ability to control inflammation. Two
specific aims are proposed. First, we will determine the role of miR-342 in Treg functions. Two newly generated
animal models in which Tregs lack or overexpress miR-342 will be used. Second, we will examine the role of
Treg-derived miR-342 in steroid resistance. Identification of the mechanisms by which glucocorticoid-induced
miR-342 regulates Treg functions will open novel opportunities to develop therapies applicable to manage severe
inflammatory conditions including steroid resistance.
