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

Abstract

After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor–mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell–mediated immune responses and open new therapeutic possibilities.

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Figure 1: Induction of miR-182 after activation of primary naive helper T lymphocytes.
Figure 2: Foxo1 is a target of miR-182.
Figure 3: Inactivation of Foxo1 by phosphorylation occurs rapidly after activation and ceases after 66 h.
Figure 4: IL-2 induces miR-182 expression.
Figure 5: Inhibition of miR-182 results in less T cell population expansion in vitro and in vivo.
Figure 6: Inhibition of miR-182 results in lower severity of OVA-induced arthritis in mice.

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Acknowledgements

We thank T. Berg (Max Planck Institute for Biochemistry) for the STAT5 inhibitor; D. Trono (École Polytechnique Fédérale de Lausanne) for the plasmid pLVTHM; H. Schliemann, T. Geske, H. Hecker-Kia, A. Peddinghaus, T. Kaiser and J. Kirsch for technical assistance; and Miltenyi Biotec for the miRXplore microarray experiments. Supported by Deutsche Forschungsgemeinschaft (GRK1121 for A.-B.S. and A.N.H.; and SFB 618, SFB 650, SFB 633 and SFB TR52), the International Max Planck Research School for Infectious Diseases and Immunology (C.H.), the Volkswagen Foundation (M.L.), the FORSYS (Forschungseinheiten zur Systembiologie) program of the Federal Ministry of Education and Research and the European Union MUGEN (Integrated Functional Genomics in Mutant Mouse Models as Tools to Investigate the Complexity of Human Immunological Disease) Network of Excellence.

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Contributions

A.-B.S. designed and did experiments, analyzed data and wrote the manuscript; C.H. did experiments and analyzed data; E.S. designed and did the OVA-induced arthritis experiments; A.A.K. and C.L. did histology; A.N.H., I.P. and M.L. designed and analyzed LCMV experiments; R.R. did the OVA-induced arthritis experiments; M.F. and T.H. analyzed CFSE measurements; J.D. and A.T. did human T cell experiments; F.F. provided cells; G.A.H. did inhibitory experiments; N.L., Z.F., U.B., A.B., J.G., H.-J.M., W.C. and N.R. did miRNA screening experiments and/or analyzed them; N.R., M.L. and Z.F. discussed the results and commented on the manuscript; F.H. revised the manuscript; A.J. constructed scrambled overexpression vector; B.H., M.M., F.-M.S. and R.B. provided technical support and conceptual advice; H.-D.C. designed experiments and supervised research; A.R. designed study, supervised research and wrote the manuscript; and M.-F.M. designed the study, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Mir-Farzin Mashreghi.

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Competing interests

U.B. and A.B. are employees of Miltenyi Biotec.

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Stittrich, AB., Haftmann, C., Sgouroudis, E. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol 11, 1057–1062 (2010). https://doi.org/10.1038/ni.1945

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