Skip to main content

Thank you for visiting 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.

Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b


MicroRNAs are small noncoding RNAs that regulate gene expression post-transcriptionally. Here we applied microRNA profiling to 17 human lymphocyte subsets to identify microRNA signatures that were distinct among various subsets and different from those of mouse lymphocytes. One of the signature microRNAs of naive CD4+ T cells, miR-125b, regulated the expression of genes encoding molecules involved in T cell differentiation, including IFNG, IL2RB, IL10RA and PRDM1. The expression of synthetic miR-125b and lentiviral vectors encoding the precursor to miR-125b in naive lymphocytes inhibited differentiation to effector cells. Our data provide an 'atlas' of microRNA expression in human lymphocytes, define subset-specific signatures and their target genes and indicate that the naive state of T cells is enforced by microRNA.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: Expression of microRNA describes and discriminates among different lymphocyte subsets.
Figure 2: Identification of putative miR-125b target genes in naive CD4+ T cells and description of their functional relationships.
Figure 3: Direct regulation by miR-125b of genes key to T cell differentiation.
Figure 4: Preservation of the naive state of CD4+ T cells by miR-125b.
Figure 5: Regulation of the differentiation of naive CD4+ T cells by miR-125b.

Accession codes


Gene Expression Omnibus


  1. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  Google Scholar 

  2. Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA 103, 2257–2261 (2006).

    Article  CAS  Google Scholar 

  3. Jopling, C.L., Yi, M., Lancaster, A.M., Lemon, S.M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005).

    Article  CAS  Google Scholar 

  4. O'Connell, R.M., Taganov, K.D., Boldin, M.P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. USA 104, 1604–1609 (2007).

    Article  CAS  Google Scholar 

  5. Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8+ T cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Lodish, H.F., Zhou, B., Liu, G. & Chen, C.Z. Micromanagement of the immune system by microRNAs. Natl. Rev. 8, 120–130 (2008).

    CAS  Google Scholar 

  8. O'Connell, R.M., Rao, D.S., Chaudhuri, A.A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122 (2010).

    Article  CAS  Google Scholar 

  9. O'Carroll, D. et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 21, 1999–2004 (2007).

    Article  CAS  Google Scholar 

  10. Cobb, B.S. et al. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J. Exp. Med. 201, 1367–1373 (2005).

    Article  CAS  Google Scholar 

  11. Koralov, S.B. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132, 860–874 (2008).

    Article  CAS  Google Scholar 

  12. Li, Q.J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).

    Article  CAS  Google Scholar 

  13. Xiao, C. et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131, 146–159 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. O'Connell, R.M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).

    Article  CAS  Google Scholar 

  17. Malumbres, R. et al. Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood 113, 3754–3764 (2009).

    Article  CAS  Google Scholar 

  18. O'Connell, R.M. et al. MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc. Natl. Acad. Sci. USA 107, 14235–14240 (2010).

    Article  CAS  Google Scholar 

  19. Bousquet, M., Harris, M.H., Zhou, B. & Lodish, H.F. MicroRNA miR-125b causes leukemia. Proc. Natl. Acad. Sci. USA 107, 21558–21563 (2010).

    Article  CAS  Google Scholar 

  20. Ooi, A.G. et al. MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets. Proc. Natl. Acad. Sci. USA 107, 21505–21510 (2010).

    Article  CAS  Google Scholar 

  21. Gefen, N. et al. HSA-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53. Leukemia 24, 89–96 (2010).

    Article  CAS  Google Scholar 

  22. Bousquet, M. et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J. Exp. Med. 205, 2499–2506 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Basso, K. et al. Identification of the human mature B cell miRNome. Immunity 30, 744–752 (2009).

    Article  CAS  Google Scholar 

  25. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).

    Article  CAS  Google Scholar 

  26. Cosmi, L. et al. CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur. J. Immunol. 30, 2972–2979 (2000).

    Article  CAS  Google Scholar 

  27. Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).

    Article  CAS  Google Scholar 

  28. Banham, A.H. Cell-surface IL-7 receptor expression facilitates the purification of FOXP3+ regulatory T cells. Trends Immunol. 27, 541–544 (2006).

    Article  CAS  Google Scholar 

  29. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    Article  CAS  Google Scholar 

  30. Kleinschek, M.A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009).

    Article  CAS  Google Scholar 

  31. Cobb, B.S. et al. A role for Dicer in immune regulation. J. Exp. Med. 203, 2519–2527 (2006).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. Li, S.C. et al. Identification of homologous microRNAs in 56 animal genomes. Genomics 96, 1–9 (2010).

    Article  CAS  Google Scholar 

  34. Mestdagh, P. et al. High-throughput stem-loop RT-qPCR miRNA expression profiling using minute amounts of input RNA. Nucleic Acids Res. 36, e143 (2008).

    Article  Google Scholar 

  35. Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nat. Struct. Mol. Biol. 17, 1169–1174 (2010).

    Article  CAS  Google Scholar 

  36. Tan, J.T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA 98, 8732–8737 (2001).

    Article  CAS  Google Scholar 

  37. Rivino, L. et al. Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J. Exp. Med. 200, 725–735 (2004).

    Article  CAS  Google Scholar 

  38. Purton, J.F. et al. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med. 204, 951–961 (2007).

    Article  CAS  Google Scholar 

  39. Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).

    Article  CAS  Google Scholar 

  40. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 6, 654–659 (2007).

    Article  Google Scholar 

Download references


We thank P. Dellabona, P. De Candia and S. Monticelli for discussions. Supported by the National Research Fund of Luxembourg (PDR-08-040 to L.W.) and the Fondazione Cariplo.

Author information

Authors and Affiliations



R.L.R., G.R. and L.W. designed and did experiments, analyzed data and wrote the manuscript; M.M. and M.C.C. did flow cytometry; R.J.P.B. did bioinformatic analyses; M.C. did statistical analyses; R.S.B., S.C., S.M., P.G., F.M., D.M., V.P. and A.R. did experiments and analyzed data; E.T. provided advice; R.D.F. discussed results, provided advice and commented on the manuscript; J.G. designed and supervised research and wrote the manuscript; and S.A. and M.P. designed the study, supervised research and wrote the manuscript.

Corresponding authors

Correspondence to Sergio Abrignani or Massimiliano Pagani.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1–4 and Supplementary Methods (PDF 1048 kb)

Supplementary Spreadsheet

RTqPCR raw CT data for all samples profiled. (TXT 218 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rossi, R., Rossetti, G., Wenandy, 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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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