The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes

Anna-Barbara Stittrich, et al. 2010. Nat immunol. 11, 1057-1062

Speaker: Yi-Wen Yang (楊逸紋)                   Time: 14:10~15:00, May 25, 2011

Commentator: Dr. Pin Ling (凌斌博士)       Place: Room 601

Abstract:

The helper T cells will undergo clonal expansion after activation by T cell antigen receptor (TCR) complex, co-receptor CD28 and IL-2 signaling. In order to expand the number of activated helper T cells, the Foxo1, which induces the cell cycle inhibitors and blocks cell cycle progression, must be inactivated in resting helper T cells. Previous studies showed that Foxo1 is inhibited by the post-translational modification of phosphorylation through TCR-CD28 signaling in the initial phase of helper T cell activation¹. However, this signaling is short-lived, and the mechanisms of repressing the Foxo1 in the late phase of clonal expansion remain unclear. In this study, the authors demonstrate a new mechanism which suggests miR-182 can regulate the Foxo1 and cause clonal expansion. They found that expression of miR-182 was evaluated after activation of naïve helper T cells. By reporter assay, they showed that Foxo1 is a target of miR-182 in the activated helper T cells. Furthermore, the expression of Foxo1 mRNA was negatively correlated with miR-182 in activated helper T cells. To confirm these findings, the authors treated activated helper T cells with miR-182 inhibitors, such as LNAs and antogomir, and found higher expression of Foxo1 in activated helper T cells. Moreover, in the presence or absence of IL-2 to activate naïve T cells, results showed that IL-2 is required for the induction of miR-182. Using chromatin-immunoprecipitaion analysis, they reported the binding of STAT5 on miR-182 locus which is activated by the IL-2R signaling² to trigger the expression of miR-182. They further demonstrated miR-182 plays an important role in clonal expansion in loss-of-function experiments both in in vitro and in vivo models. Furthermore, in the ovalbumin-induced arthritis mouse model, the authors showed that inhibition of miR-182 decreased the viable helper T cells and disease severity of arthritis. In conclusion, the authors demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell -mediated immune response and open new therapeutic possibility.

References:

1. Peng, S.L. 2008. Foxo in the immune system. Oncogene 27, 2337–2344.
2. Rochman, Y. et al. 2009. New insights into the regulation of T cells by γ c family cytokines. Nat. Rev. Immunol. 9, 480–490.