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.

Physiological and pathological roles for microRNAs in the immune system

Key Points

  • MicroRNAs (miRNAs) are expressed by cells that constitute the immune system, and they function by repressing specific mRNA targets at the post-transcriptional level.

  • The biosynthesis of miRNAs involves several levels of regulation, some of which are influenced by inflammation.

  • Specific miRNAs modulate haematopoietic cell development.

  • miRNAs regulate both innate and adaptive immune responses.

  • miRNA expression levels are dysregulated in diseases of immunological origin, such as cancer and autoimmunity. Altered miRNA expression can subsequently exacerbate disease severity.

  • Research into miRNA is a recent development, and therefore many aspects of miRNA biology remain unexplored.

Abstract

Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: MicroRNA expression and function are regulated at three levels and influenced by inflammation and stress.
Figure 2: MicroRNA-mediated regulation of early haematopoietic cell development.
Figure 3: MicroRNA-mediated regulation of myeloid cell development and function.
Figure 4: MicroRNA-mediated regulation of T cell development and function.
Figure 5: MicroRNA-mediated regulation of B cell development and function.
Figure 6: Mechanisms of microRNA contribution to cancer.

References

  1. 1

    Baltimore, D., Boldin, M. P., O'Connell, R. M., Rao, D. S. & Taganov, K. D. MicroRNAs: new regulators of immune cell development and function. Nature Immunol. 9, 839–845 (2008).

    CAS  Google Scholar 

  2. 2

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

    CAS  Google Scholar 

  3. 3

    Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006).

    CAS  Google Scholar 

  4. 4

    Winter, J., Jung, S., Keller, S., Gregory, R. I. & Diederichs, S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature Cell Biol. 11, 228–234 (2009).

    CAS  PubMed  Google Scholar 

  5. 5

    Ballarino, M. et al. Coupled RNA processing and transcription of intergenic primary microRNAs. Mol. Cell. Biol. 29, 5632–5638 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Chekulaeva, M. & Filipowicz, W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr. Opin. Cell Biol. 21, 452–460 (2009).

    CAS  PubMed  Google Scholar 

  7. 7

    Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).

    CAS  PubMed  Google Scholar 

  8. 8

    Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. & Parker, R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nature Cell Biol. 7, 719–723 (2005).

    CAS  PubMed  Google Scholar 

  9. 9

    Ramachandran, V. & Chen, X. Degradation of microRNAs by a family of exoribonucleases in Arabidopsis. Science 321, 1490–1492 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Chatterjee, S. & Grosshans, H. Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature 461, 546–549 (2009).

    CAS  PubMed  Google Scholar 

  11. 11

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006). References 11 and 12 are the initial studies showing that specific miRNAs are upregulated in response to a broad range of inflammatory stimuli.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Gruber, J. J. et al. Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation. Cell 138, 328–339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nature Struct. Mol. Biol. 13, 13–21 (2006).

    CAS  Google Scholar 

  16. 16

    Suzuki, H. I. et al. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009).

    CAS  PubMed  Google Scholar 

  17. 17

    Ruggiero, T. et al. LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J. 23, 2898–2908 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Trabucchi, M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459, 1010–1014 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Piskounova, E. et al. Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J. Biol. Chem. 283, 21310–21314 (2008).

    CAS  PubMed  Google Scholar 

  20. 20

    Hagan, J. P., Piskounova, E. & Gregory, R. I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nature Struct. Mol. Biol. 16, 1021–1025 (2009).

    CAS  Google Scholar 

  21. 21

    Heo, I. et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 138, 696–708 (2009).

    CAS  PubMed  Google Scholar 

  22. 22

    Wiesen, J. L. & Tomasi, T. B. Dicer is regulated by cellular stresses and interferons. Mol. Immunol. 46, 1222–1228 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Weinmann, L. et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 136, 496–507 (2009).

    CAS  PubMed  Google Scholar 

  24. 24

    Leung, A. K., Calabrese, J. M. & Sharp, P. A. Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc. Natl Acad. Sci. USA 103, 18125–18130 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Gangaraju, V. K. & Lin, H. MicroRNAs: key regulators of stem cells. Nature Rev. Mol. Cell Biol. 10, 116–125 (2009).

    CAS  Google Scholar 

  27. 27

    Georgantas, R. W. et al. CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc. Natl Acad. Sci. USA 104, 2750–2755 (2007).

    CAS  PubMed  Google Scholar 

  28. 28

    Merkerova, M., Vasikova, A., Belickova, M. & Bruchova, H. MicroRNA expression profiles in umbilical cord blood cell lineages. Stem Cells Dev. 12 May 2009 (doi:10.1089/scd.2009.0071).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Argiropoulos, B. & Humphries, R. K. Hox genes in hematopoiesis and leukemogenesis. Oncogene 26, 6766–6776 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Garzon, R. et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc. Natl Acad. Sci. USA 105, 3945–3950 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Mansfield, J. H. et al. MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nature Genet. 36, 1079–1083 (2004).

    CAS  PubMed  Google Scholar 

  32. 32

    Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).

    CAS  Google Scholar 

  33. 33

    Popovic, R. et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113, 3314–3322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Shen, W. F., Hu, Y. L., Uttarwar, L., Passegue, E. & Largman, C. MicroRNA-126 regulates HOXA9 by binding to the homeobox. Mol. Cell. Biol. 28, 4609–4619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Li, Z. et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc. Natl Acad. Sci. USA 105, 15535–15540 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Felli, N. et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc. Natl Acad. Sci. USA 102, 18081–18086 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Velu, C. S., Baktula, A. M. & Grimes, H. L. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood 113, 4720–4728 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Hock, H. et al. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 18, 109–120 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    O'Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009).

    CAS  PubMed  Google Scholar 

  40. 40

    O'Connell, R. M. et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J. Exp. Med. 205, 585–594 (2008). This is the first in vivo evidence that miR-155 links inflammation and haematopoietic malignancy.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Fukao, T. et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 129, 617–631 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Johnnidis, J. B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008). This is the first report that genetic deletion of miRNAs can influence myeloid cell development and function in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Rosenbauer, F. & Tenen, D. G. Transcription factors in myeloid development: balancing differentiation with transformation. Nature Rev. Immunol. 7, 105–117 (2007).

    CAS  Google Scholar 

  44. 44

    Fontana, L. et al. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nature Cell Biol. 9, 775–787 (2007). A clear demonstration of the interaction between specific miRNAs and transcription factors during haematopoietic cell development.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Rosa, A. et al. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc. Natl Acad. Sci. USA 104, 19849–19854 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Fazi, F. et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell 123, 819–831 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Sheedy, F. J. et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nature Immunol. 29 Nov 2009 (doi:10.1038/ni.1828).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Liu, G. et al. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc. Natl Acad. Sci. USA 106, 15819–15824 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bazzoni, F. et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc. Natl Acad. Sci. USA 106, 5282–5287 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Tam, W., Ben-Yehuda, D. & Hayward, W. S. bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. Mol. Cell. Biol. 17, 1490–1502 (1997). An early study linking a miRNA containing non-coding RNA to lymphoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

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

    CAS  Google Scholar 

  52. 52

    Gatto, G. et al. Epstein–Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-κB pathway. Nucleic Acids Res. 36, 6608–6619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Yin, Q., Wang, X., McBride, J., Fewell, C. & Flemington, E. B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element. J. Biol. Chem. 283, 2654–2662 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Hou, J. et al. MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183, 2150–2158 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Ceppi, M. et al. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc. Natl Acad. Sci. USA 106, 2735–2740 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Lu, F. et al. Epstein–Barr virus-induced miR-155 attenuates NF-κB signaling and stabilizes latent virus persistence. J. Virol. 82, 10436–10443 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Costinean, S. et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein β are targeted by miR-155 in B cells of Eμ-MiR-155 transgenic mice. Blood 114, 1374–1382 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Sly, L. M., Rauh, M. J., Kalesnikoff, J., Song, C. H. & Krystal, G. LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21, 227–239 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Androulidaki, A. et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31, 220–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Hashimi, S. T. et al. MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 114, 404–414 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007). References 51 and 61 report the first miRNA knockout mice and identify an important role for miR-155 in antibody production.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Martinez-Nunez, R. T., Louafi, F., Friedmann, P. S. & Sanchez-Elsner, T. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J. Biol. Chem. 284, 16334–16342 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Stern-Ginossar, N. et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nature Immunol. 9, 1065–1073 (2008).

    CAS  Google Scholar 

  64. 64

    Nachmani, D., Stern-Ginossar, N., Sarid, R. & Mandelboim, O. Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 5, 376–385 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Stern-Ginossar, N. et al. Host immune system gene targeting by a viral miRNA. Science 317, 376–381 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Fedeli, M. et al. Dicer-dependent microRNA pathway controls invariant NKT cell development. J. Immunol. 183, 2506–2512 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Zhou, L. et al. Tie2cre-induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development. Proc. Natl Acad. Sci. USA 106, 10266–10271 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Merkerova, M., Belickova, M. & Bruchova, H. Differential expression of microRNAs in hematopoietic cell lineages. Eur. J. Haematol. 81, 304–310 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Monticelli, S. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 6, R71 (2005).

    PubMed  PubMed Central  Google Scholar 

  70. 70

    Wu, H. et al. miRNA profiling of naive, effector and memory CD8 T cells. PLoS One 2, e1020 (2007).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Muljo, S. A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005). References 72 and 73 show an important role for the miRNA pathway in the development of mature T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nature Immunol. 9, 405–414 (2008). This paper provides the first evidence that a specific miRNA can promote an autoimmune phenotype in vivo.

    CAS  Google Scholar 

  75. 75

    Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007). An elegant demonstration that miRNAs can modulate signal transduction pathways during T cell development.

    CAS  Google Scholar 

  76. 76

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

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

    CAS  Google Scholar 

  78. 78

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

    CAS  Google Scholar 

  79. 79

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Zhou, X. et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983–1991 (2008). References 79–81 show a crucial role for miRNAs in T Reg cell biology and the prevention of spontaneous autoimmunity.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Kohlhaas, S. et al. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J. Immunol. 182, 2578–2582 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

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

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Huang, B. et al. miR-142-3p restricts cAMP production in CD4+CD25 T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 10, 180–185 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Tan, L. P. et al. miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes. Lab. Invest. 89, 708–716 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

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

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Zhang, J. et al. Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood 113, 4586–4594 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Xiao, C. & Rajewsky, K. MicroRNA control in the immune system: basic principles. Cell 136, 26–36 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004). This is the first study showing that miRNAs can direct haematopoietic cell development.

    CAS  Google Scholar 

  91. 91

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

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132, 875–886 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Zhou, B., Wang, S., Mayr, C., Bartel, D. P. & Lodish, H. F. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc. Natl Acad. Sci. USA 104, 7080–7085 (2007).

    CAS  PubMed  Google Scholar 

  94. 94

    Xiao, C. et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131, 146–159 (2007). This paper shows that early B cell development is regulated by specific miRNAs.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Vigorito, E. et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27, 847–859 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Dorsett, Y. et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc–Igh translocation. Immunity 28, 630–638 (2008). This was the first group to mutate a miRNA-binding site in the 3′ UTR of a target mRNA in the germline and demonstrate derepression of this miRNA target in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Teng, G. et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28, 621–629 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004). This report describes the important observation that miRNA genes are found at locations in the genome that are commonly altered in cancer.

    CAS  PubMed  Google Scholar 

  100. 100

    Garzon, R., Calin, G. A. & Croce, C. M. MicroRNAs in cancer. Annu. Rev. Med. 60, 167–179 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005). This paper shows that miRNA expression profiles can be used to categorize unique types of cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Roehle, A. et al. MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas. Br. J. Haematol. 142, 732–744 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Mi, S. et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc. Natl Acad. Sci. USA 104, 19971–19976 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Marcucci, G. et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358, 1919–1928 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Calin, G. A. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002). This is the initial study linking the deletion of specific miRNAs to the development of human cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Zenz, T. et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 113, 3801–3808 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Pigazzi, M., Manara, E., Baron, E. & Basso, G. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res. 69, 2471–2478 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Pekarsky, Y. et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res. 66, 11590–11593 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Fazi, F. et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12, 457–466 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Garzon, R. et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113, 6411–6418 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Mendell, J. T. miRiad roles for the miR-17-92 cluster in development and disease. Cell 133, 217–222 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005). This study shows that miRNAs can collaborate with known oncogenes to elicit tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Fulci, V. et al. Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 109, 4944–4951 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Eis, P. S. et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl Acad. Sci. USA 102, 3627–3632 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    van den Berg, A. et al. High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Genes Chromosomes Cancer 37, 20–28 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Costinean, S. et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proc. Natl Acad. Sci. USA 103, 7024–7029 (2006). The first study to demonstrate that a single miRNA is sufficient to cause a B cell malignancy in vivo.

    CAS  Google Scholar 

  118. 118

    Gottwein, E. et al. A viral microRNA functions as an orthologue of cellular miR-155. Nature 450, 1096–1099 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Pauley, K. M., Cha, S. & Chan, E. K. MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun. 32, 189–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Pauley, K. M. et al. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res. Ther. 10, R101 (2008).

    PubMed  PubMed Central  Google Scholar 

  121. 121

    Alsaleh, G. et al. Bruton's tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J. Immunol. 182, 5088–5097 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Otaegui, D. et al. Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One 4, e6309 (2009).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nature Immunol. 10, 1162–1169 (2009).

    CAS  Google Scholar 

  124. 124

    Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299–303 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Lu, T. X., Munitz, A. & Rothenberg, M. E. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J. Immunol. 182, 4994–5002 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Sharma, A. et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc. Natl Acad. Sci. USA 106, 5761–5766 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).

    CAS  Google Scholar 

Download references

Acknowledgements

The writing of this review was supported by the United States National Institutes of Health (US NIH)(D.B), the Irvington Institute Fellowship Program of the Cancer Research Institute (R.M.O'C.), the US NIH 1K08CA133521 (D.S.R.) and the Graduate Research Fellowship Program of the National Science Foundation (A.A.C.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to David Baltimore.

Ethics declarations

Competing interests

D.B. is a director and Chair of the Scientific Advisory Board of Regulus, a company devoted to microRNA therapeutics. R.M.O'C. has consulted for Regulus. D.S.R. and A.A.C. have no competing financial interests.

Related links

Related links

FURTHER INFORMATION

David Baltimore's homepage

Glossary

3′ untranslated region

The sequence of a messenger RNA that is located downstream of the stop codon.

RNA-induced silencing complex

A multicomponent ribonucleoprotein complex, comprising miRNAs or siRNAs and Argonaute proteins, that silences the expression of proteins from target mRNAs by cleavage or other unknown mechanisms depending on the complementarity of mRNA sequences to the packaged small RNAs.

Processing bodies

Cytoplasmic foci that are thought to store and degrade translationally repressed RNA.

p53

A tumour suppressor protein that is mutated in 50% of all human cancers. The p53 protein is a transcription factor that is activated by DNA damage, anoxia, expression of certain oncogenes and several other stress stimuli. Target genes activated by p53 regulate cell cycle arrest, apoptosis, cell senescence and DNA repair.

Retinoic acid-inducible gene I

A cytoplasmic pathogen sensor that recognizes viral double-stranded RNA molecules and triggers an antiviral response.

Germinal centre

A lymphoid structure that arises within follicles after immunization with, or exposure to, a T cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Affinity maturation

The somatic mutation process by which B cells are selected for survival and proliferation on the basis of their increased affinity for antigen.

Class switching

The somatic recombination process by which the class of immunoglobulin is switched from IgM to IgG, IgA or IgE.

Regulatory T (TReg) cells

A small population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and FOXP3. They have suppressive regulatory activity towards other T cells that are stimulated through their T cell receptor. An absence of TReg cells or their dysfunction is associated with severe autoimmunity.

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T cell and B cell receptors.

B-1 B cells

A subset of self-renewing B cells found mainly in the peritoneal cavity and the pleural cavity. They recognize self components, as well as common bacterial antigens, and they secrete antibodies that generally have low affinity and broad specificity.

B-2 B cells

Conventional B cells. These cells reside in secondary lymphoid organs and secrete antibodies with high affinity and narrow specificity.

RAG proteins

RAG1 and RAG2 are proteins that mediate V(D)J recombination in preB cells and thymocytes, which allows the production of antibodies and T cell receptors, respectively.

Activation-induced cytidine deaminase

(AID). An RNA-editing enzyme that is necessary for antibody affinity maturation and class switching.

Fragile site

A site in a chromosome that is susceptible to chromosome breakage and fusion with other chromosomes.

Epigenetic regulation

The alteration of gene expression through transcriptional mechanisms (owing to promoter methylation) or post-transcriptional mechanisms instead of 'genetic' alteration of sequences of bases in genomic DNA.

AML1–ETO

The fusion protein that is generated by the t(8;21) translocation found in some acute myeloid leukaemias.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

O'Connell, R., Rao, D., Chaudhuri, A. et al. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10, 111–122 (2010). https://doi.org/10.1038/nri2708

Download citation

Further reading

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