Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells

Abstract

Distinct CD4+ T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (Treg cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-β (TGF-β) in inducible Treg cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible Treg cells into follicular helper T cells. We also found that miR-10a limited differentiation into the TH17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: High expression of miR-10a in nTreg cells and induction of miR-10a by RA and TGF-β.
Figure 2: Direct targeting of Bcl-6 and Ncor2 by miR-10a and downregulation of protein expression.
Figure 3: Conversion of iTreg cells into TFH cells in Peyer's patches.
Figure 4: Conversion of iTreg cells into TFH cells constrained by miR-10a.
Figure 5: RA has biphasic effects on TH17 differentiation.
Figure 6: Onset of experimental autoimmune encephalomyelitis delayed (but not abrogated) by miR-10a.
Figure 7: TH17 differentiation constrained by miR-10a in the presence of RA.
Figure 8: Ncor2 and Bcl-6 regulate IL-17A in a T-bet-dependent manner.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    CAS  PubMed  Google Scholar 

  3. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. O'Shea, J.J. & Paul, W.E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee, Y.K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bending, D. et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J. Clin. Invest. 119, 565–572 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hegazy, A.N. et al. Interferons direct Th2 cell reprogramming to generate a stable GATA-3+T-bet+ cell subset with combined Th2 and Th1 cell functions. Immunity 32, 116–128 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Rubtsov, Y.P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Zaretsky, A.G. et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991–999 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  12. Lu, K.T. et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35, 622–632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Rossi, R.L. et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nat. Immunol. 12, 796–803 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Steiner, D.F. et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity 35, 169–181 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ma, F. et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat. Immunol. 12, 861–869 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Stittrich, A.B. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Lu, L.F. et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914–929 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10, 1252–1259 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Lu, L.F. et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30, 80–91 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thai, T.H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Chong, M.M., Rasmussen, J.P., Rudensky, A.Y. & Littman, D.R. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 2005–2017 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liston, A., Lu, L.F., O'Carroll, D., Tarakhovsky, A. & Rudensky, A.Y. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J. Exp. Med. 205, 1993–2004 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou, X. et al. Selective miRNA disruption in Treg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983–1991 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Muljo, S.A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kuchen, S. et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32, 828–839 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Meseguer, S., Mudduluru, G., Escamilla, J.M., Allgayer, H. & Barettino, D. Micro-RNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). J. Biol. Chem. 286, 4150–4164 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nurieva, R.I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Chen, J.D. & Evans, R.M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454–457 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Dhordain, P. et al. Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc. Natl. Acad. Sci. USA 94, 10762–10767 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kikuchi, M. et al. Identification of negative regulatory regions within the first exon and intron of the BCL6 gene. Oncogene 19, 4941–4945 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat. Methods 6, 63–66 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Linterman, M.A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187, 4553–4560 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Hall, J.A. et al. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor α. Immunity 34, 435–447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. DePaolo, R.W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kane, M.A., Folias, A.E., Wang, C. & Napoli, J.L. Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry. Anal. Chem. 80, 1702–1708 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Manel, N., Unutmaz, D. & Littman, D.R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat. Immunol. 9, 641–649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lazarevic, V. et al. T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat. Immunol. 12, 96–104 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Mahony, S. et al. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol. 12, R2 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  52. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Elias, K.M. et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111, 1013–1020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ghoreschi, K. et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467, 967–971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Y. Belkaid, W. Chen and A. Villarino for reading this manuscript; K. Moro and T. Tamachi for advice on manipulating Peyer's patches; L. Naldini (San Raffaele Institute) for the LV-SFFV lentiviral vector; and J. Simone and J. Lay for cell sorting. Supported by the Japan Society for the Promotion of Science (Research Fellowship for Japanese Biomedical and Behavioral Researchers at the US National Institutes of Health to H.T. and K.H.), the Instituto Pasteur-Fondazione Cenci-Bolognetti (G.S.) and the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases.

Author information

Authors and Affiliations

Authors

Contributions

H.T. designed, did, analyzed and interpreted all the experiments and wrote the manuscript; T.K., S.N., K.H., G.S., S.K. and L.W. helped with experiments; Y.K. contributed to data interpretation, helped with experiments and wrote the manuscript; S.A.M. and R.C. contributed to experimental design and provided suggestions; and J.J.O. contributed to experimental design, analyzed and interpreted all acquired data and wrote the manuscript.

Corresponding author

Correspondence to John J O'Shea.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 387 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, H., Kanno, T., Nakayamada, S. et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol 13, 587–595 (2012). https://doi.org/10.1038/ni.2286

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2286

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing