Review Article | Published:

MicroRNAs as regulatory elements in immune system logic

Nature Reviews Immunology volume 16, pages 279294 (2016) | Download Citation

  • A Corrigendum to this article was published on 23 May 2016

This article has been updated

Abstract

MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs.

Key points

  • Several factors contribute to haematopoietic cell fate decisions, including transcription factors and microRNAs (miRNAs), which are a class of small non-coding RNAs that negatively regulate gene expression.

  • Several miRNAs have been found to participate in network motif architectures that influence haematopoietic cell fate decisions. These miRNAs may further serve to buffer target protein expression in response to environment stress or set protein expression thresholds at key developmental checkpoints.

  • Several miRNAs have recently been found to contribute to haematopoietic stem cell (HSC) survival and function. These miRNAs regulate diverse processes, including HSC reconstitution potential, self-renewal, differentiation, autophagy, apoptosis and response to inflammatory signals.

  • Innate immune cells, particularly macrophages and granulocytes, are perhaps the most well-studied system for miRNA regulation of immune development and function. However, little is known about the role of miRNAs in gene networks underlying megakaryocyte and erythroid cell development.

  • Several mechanisms have been uncovered by which miRNAs regulate adaptive immune cell development and function. These mechanisms include the regulation of key regulators of developmental checkpoints, fine-tuning of signalling pathways and modulation of the immune response.

  • Aberrant miRNA expression can have severe pathological consequences, including the development of autoimmune disease and cancer. Recent advances in gene-editing technology hold promise for modulating miRNA expression for therapeutic purposes.

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Change history

  • 23 May 2016

    In the original version of this article, an incorrect arrowhead was used in Figure 2b, suggesting that factor Y negatively regulates microRNA X. This has now been corrected in the online version of the article to show that factor Y positively regulates microRNA X. Also, miR-146a was incorrectly listed as miR-46a in figure 5a, and this has now been corrected. The authors and Nature Reviews Immunology apologize for these errors.

References

  1. 1.

    , & Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

  2. 2.

    , , & A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

  3. 3.

    & Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

  4. 4.

    , , , & Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005).

  5. 5.

    et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011).

  6. 6.

    et al. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell 11, 302–317 (2012).

  7. 7.

    et al. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat. Immunol. 14, 756–763 (2013).

  8. 8.

    et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA Methylome analysis. Cell Stem Cell 15, 507–522 (2014).

  9. 9.

    et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat. Immunol. 4, 866–873 (2003).

  10. 10.

    , & Determinants of lymphoid-myeloid lineage diversification. Annu. Rev. Immunol. 24, 705–738 (2006).

  11. 11.

    et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 407, 383–386 (2000).

  12. 12.

    et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).

  13. 13.

    et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 154, 1112–1126 (2013).

  14. 14.

    Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell 6, 203–207 (2010).

  15. 15.

    et al. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1, 428–442 (2007).

  16. 16.

    Defining the pathways of early adult hematopoiesis. Cell Stem Cell 1, 357–358 (2007).

  17. 17.

    et al. Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell 1, 416–427 (2007).

  18. 18.

    et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature 496, 229–232 (2013).

  19. 19.

    , & Balancing dormant and self-renewing hematopoietic stem cells. Curr. Opin. Genet. Dev. 19, 461–468 (2009).

  20. 20.

    et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

  21. 21.

    & The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

  22. 22.

    et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 17, 35–46 (2015).

  23. 23.

    et al. Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. Immunity 26, 407–419 (2007).

  24. 24.

    , & Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1, 635–645 (2007).

  25. 25.

    et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

  26. 26.

    & Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nature reviews. Immunology 11, 685–692 (2011).

  27. 27.

    , & Inflammatory signals regulate hematopoietic stem cells. Trends Immunol. 32, 57–65 (2011).

  28. 28.

    et al. Cutting edge: bacterial infection induces hematopoietic stem and progenitor cell expansion in the absence of TLR signaling. J. Immunol. 184, 2247–2251 (2010).

  29. 29.

    et al. Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling. Cell Host Microbe 15, 779–791 (2014).

  30. 30.

    et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

  31. 31.

    et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J. Immunol. 186, 5367–5375 (2011).

  32. 32.

    , , , & Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010).

  33. 33.

    et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014).

  34. 34.

    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).

  35. 35.

    et al. MicroRNA miR-125a controls hematopoietic stem cell number. Proc. Natl Acad. Sci. USA 107, 14229–14234 (2010).

  36. 36.

    et al. The microRNA-132 and microRNA-212 cluster regulates hematopoietic stem cell maintenance and survival with age by buffering FOXO3 expression. Immunity 42, 1021–1032 (2015).

  37. 37.

    et al. MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc. Natl Acad. Sci. USA 107, 14235–14240 (2010). This study highlights the role of several miRNAs in regulating HSC function as measured by bone marrow engraftment.

  38. 38.

    et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

  39. 39.

    et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).

  40. 40.

    et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24, 801–812 (2006).

  41. 41.

    et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14, 445–459 (2014).

  42. 42.

    , & The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).

  43. 43.

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

  44. 44.

    & Dicer is regulated by cellular stresses and interferons. Mol. Immunol. 46, 1222–1228 (2009).

  45. 45.

    et al. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009). This study describes a mechanism by which miRNA processing is altered in response to environmental stress.

  46. 46.

    , & Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc. Natl Acad. Sci. USA 103, 18125–18130 (2006).

  47. 47.

    & Regulation of miRNA biogenesis and turnover in the immune system. Immunol. Rev. 253, 304–316 (2013).

  48. 48.

    & MicroRNAs in stress signaling and human disease. Cell 148, 1172–1187 (2012).

  49. 49.

    & MicroRNA functions in stress responses. Mol. Cell 40, 205–215 (2010).

  50. 50.

    , & MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun. 32, 189–194 (2009).

  51. 51.

    , & OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467, 86–90 (2010). This is the first model for oncomir addiction in haematopoietic malignancies.

  52. 52.

    & Oncomirs — microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).

  53. 53.

    et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat. Immunol. 11, 635–643 (2010).

  54. 54.

    et al. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate. Proc. Natl Acad. Sci. USA 109, 21028–21033 (2012).

  55. 55.

    et al. Circuitry and dynamics of human transcription factor regulatory networks. Cell 150, 1274–1286 (2012).

  56. 56.

    & Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).

  57. 57.

    & MicroRNAs as regulators of differentiation and cell fate decisions. Cell Stem Cell 7, 36–41 (2010).

  58. 58.

    et al. A Single miRNA-mRNA interaction affects the immune response in a context- and cell-type-specific manner. Immunity 43, 52–64 (2015).

  59. 59.

    , , , & MicroRNA-based single-gene circuits buffer protein synthesis rates against perturbations. ACS Synthet. Biol. 3, 324–331 (2014).

  60. 60.

    et al. Gene expression. MicroRNA control of protein expression noise. Science 348, 128–132 (2015).

  61. 61.

    et al. microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes. PLoS Genet. 11, e1005020 (2015).

  62. 62.

    , & Dampening of expression oscillations by synchronous regulation of a microRNA and its target. Nat. Genet. 45, 1337–1344 (2013). This study quantitatively describes how miRNAs can buffer oscillations in protein expression.

  63. 63.

    et al. MicroRNAs can generate thresholds in target gene expression. Nat. Genet. 43, 854–859 (2011). This study quantitatively describes how miRNAs can set thresholds for target gene expression.

  64. 64.

    & Understanding cooperativity of microRNAs via microRNA association networks. BMC genomics 14 (Suppl. 5), S17 (2013).

  65. 65.

    Network motifs: theory and experimental approaches. Nat. Rev. Genet. 8, 450–461 (2007). This is an overview of network motifs and their biological implications.

  66. 66.

    & MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev. 24, 1339–1344 (2010).

  67. 67.

    & The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

  68. 68.

    et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130 (2015).

  69. 69.

    et al. MicroRNAs play a role in the development of human hematopoietic stem cells. J. Cell. Biochem. 104, 805–817 (2008).

  70. 70.

    et al. Combined characterization of microRNA and mRNA profiles delineates early differentiation pathways of CD133+ and CD34+ hematopoietic stem and progenitor cells. Stem Cells 29, 847–857 (2011).

  71. 71.

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

  72. 72.

    et al. Genetic screen identifies microRNA cluster 99b/let-7e/125a as a regulator of primitive hematopoietic cells. Blood 119, 377–387 (2012).

  73. 73.

    et al. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proc. Natl Acad. Sci. USA 109, 4233–4238 (2012).

  74. 74.

    et al. The microRNA-212/132 cluster regulates B cell development by targeting Sox4. J. Exp. Med. 212, 1679–1692 (2015).

  75. 75.

    et al. Regulation of miR-17-92a cluster processing by the microRNA binding protein SND1. FEBS Lett. 587, 2405–2411 (2013).

  76. 76.

    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).

  77. 77.

    et al. Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias. Blood 124, 1502–1512 (2014).

  78. 78.

    et al. miR-99a/100125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling. Genes Dev. 28, 858–874 (2014).

  79. 79.

    , , & Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6, 265–278 (2010).

  80. 80.

    et al. Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 9, 345–356 (2011).

  81. 81.

    et al. microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia. J. Exp. Med. 207, 475–489 (2010).

  82. 82.

    et al. miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a. Blood 125, 2206–2216 (2015).

  83. 83.

    et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 13, 87–101 (2013).

  84. 84.

    et al. Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome. Proc. Natl Acad. Sci. USA 107, 9783–9788 (2010).

  85. 85.

    et al. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci. Transl Med. 2, 58ra84 (2010).

  86. 86.

    et al. Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell 11, 799–811 (2012).

  87. 87.

    et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell 29, 214–228 (2016).

  88. 88.

    , , , & MicroRNA-126 regulates HOXA9 by binding to the homeobox. Mol. Cell. Biol. 28, 4609–4619 (2008).

  89. 89.

    et al. The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nature Cell Biol. 15, 916–925 (2013).

  90. 90.

    , , , & Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012). This study demonstrates how altering the post-transcriptional processing of a specific miRNA can reprogramme adult haematopoietic cells to fetal haematopoiesis.

  91. 91.

    & Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

  92. 92.

    , & MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat. Rev. Immunol. 11, 163–175 (2011).

  93. 93.

    , , & 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). This is the first study to demonstrate induction of miRNAs in response to inflammatory stimuli.

  94. 94.

    et al. NF-κB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc. Natl Acad. Sci. USA 108, 9184–9189 (2011).

  95. 95.

    , , , & MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. eLife 2, e00537 (2013).

  96. 96.

    et al. miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal. Cell Cycle) 9, 3277–3285 (2010).

  97. 97.

    et al. STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling. Nature Commun. 6, 8928 (2015).

  98. 98.

    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).

  99. 99.

    , & microRNA regulation of inflammatory responses. Annu. Rev. Immunol. 30, 295–312 (2012).

  100. 100.

    , & MicroRNA function in myeloid biology. Blood 118, 2960–2969 (2011).

  101. 101.

    et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc. Natl Acad. Sci. USA 112, 7231–7236 (2015).

  102. 102.

    , , & Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009).

  103. 103.

    , , , & MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007).

  104. 104.

    et al. Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner. Cell Stem Cell 15, 51–65 (2014).

  105. 105.

    , & MicroRNAs regulate dendritic cell differentiation and function. J. Immunol. 187, 3911–3917 (2011).

  106. 106.

    , , & miRNA-based mechanism for the commitment of multipotent progenitors to a single cellular fate. Proc. Natl Acad. Sci. USA 107, 15804–15809 (2010).

  107. 107.

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

  108. 108.

    et al. IL-10 inhibits miR-155 induction by toll-like receptors. J. Biol. Chem. 285, 20492–20498 (2010).

  109. 109.

    et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J. Exp. Med. 205, 585–594 (2008). This is one of the first studies to demonstrate that aberrant miRNA expression can lead to myeloproliferative disorders.

  110. 110.

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

  111. 111.

    et al. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Blood 115, 1768–1778 (2010).

  112. 112.

    et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008). This is the first demonstration of a miRNA that can contribute to granulocyte development.

  113. 113.

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

  114. 114.

    et al. Transcriptional fine-tuning of microRNA-223 levels directs lineage choice of human hematopoietic progenitors. Cell Death Differ. 21, 290–301 (2014).

  115. 115.

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

  116. 116.

    , & Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood 113, 4720–4728 (2009).

  117. 117.

    et al. MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-β1 stimulation in granulocytic precursors. Blood 118, 6649–6659 (2011).

  118. 118.

    et al. Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Blood 16, 517–524 (2015).

  119. 119.

    et al. Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling. J. Immunol. 187, 6171–6175 (2011).

  120. 120.

    , , & miR-150 regulates the development of NK and iNKT cells. J. Exp. Med. 208, 2717–2731 (2011).

  121. 121.

    et al. MicroRNA function in NK-cell biology. Immunol. Rev. 253, 40–52 (2013).

  122. 122.

    et al. Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms. Blood 120, 3575–3585 (2012).

  123. 123.

    et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev. Cell 14, 843–853 (2008).

  124. 124.

    et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc. Natl Acad. Sci. USA 103, 5078–5083 (2006).

  125. 125.

    et al. The miR-144/451 locus is required for erythroid homeostasis. J. Exp. Med. 207, 1351–1358 (2010).

  126. 126.

    et al. MiR-223 deficiency increases eosinophil progenitor proliferation. J. Immunol. 190, 1576–1582 (2013).

  127. 127.

    et al. MicroRNA-221-222 regulate the cell cycle in mast cells. J. Immunol. 182, 433–445 (2009).

  128. 128.

    et al. MicroRNAs in B-cells: from normal differentiation to treatment of malignancies. Oncotarget 6, 7–25 (2015).

  129. 129.

    & MicroRNA regulation of T-lymphocyte immunity: modulation of molecular networks responsible for T-cell activation, differentiation, and development. Crit. Rev. Immunol. 33, 435–476 (2013).

  130. 130.

    , & MicroRNA regulation of T-cell development. Immunol. Rev. 253, 53–64 (2013).

  131. 131.

    , & Regulation of B-cell development and function by microRNAs. Immunol. Rev. 253, 25–39 (2013).

  132. 132.

    , , , & The role of microRNAs in B-cell development and function. Cell. Mol. Immunol. 10, 107–112 (2013).

  133. 133.

    & MicroRNA regulation of T-cell differentiation and function. Immunol. Rev. 253, 65–81 (2013).

  134. 134.

    & MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat. Rev. Immunology 13, 666–678 (2013).

  135. 135.

    & The transcriptional regulation of B cell lineage commitment. Immunity 26, 715–725 (2007).

  136. 136.

    & Transcriptional networks in developing and mature B cells. Nat. Rev. Immunol. 5, 497–508 (2005).

  137. 137.

    , , , & Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002).

  138. 138.

    & Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity 11, 21–31 (1999).

  139. 139.

    , , & Pax5: the guardian of B cell identity and function. Nat. Immunol. 8, 463–470 (2007).

  140. 140.

    , , & Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Immunity 17, 781–793 (2002).

  141. 141.

    et al. Sox4 is required for the survival of pro-B cells. J. Immunol. 190, 2080–2089 (2013).

  142. 142.

    et al. Integrated genetic approaches identify the molecular mechanisms of Sox4 in early B-cell development: intricate roles for RAG1/2 and CK1ɛ. Blood 123, 4064–4076 (2014).

  143. 143.

    , , & MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004). This is the first study to show that miRNAs can modulate immune cell development.

  144. 144.

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

  145. 145.

    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).

  146. 146.

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

  147. 147.

    et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132, 860–874 (2008). This is an early study that details the impact of miRNA deletion on B cell development and function.

  148. 148.

    , , , & 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).

  149. 149.

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

  150. 150.

    , , & Expression of the c-myb proto-oncogene during cellular proliferation. Nature 319, 374–380 (1986).

  151. 151.

    et al. Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat. Genet. 39, 593–595 (2007).

  152. 152.

    et al. MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity 33, 48–59 (2010).

  153. 153.

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

  154. 154.

    , , & Molecular programming of B cell memory. Nat. Rev. Immunol. 12, 24–34 (2012).

  155. 155.

    , , , & IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells. J. Immunol. 190, 1827–1836 (2013).

  156. 156.

    , , & The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

  157. 157.

    , , , & BLIMP-1 and STAT3 counterregulate microRNA-21 during plasma cell differentiation. J. Immunol. 189, 253–260 (2012).

  158. 158.

    et al. The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation. J. Exp. Med. 211, 2183–2198 (2014).

  159. 159.

    et al. miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur. J. Immunol. 45, 1206–1215 (2015).

  160. 160.

    , , , & B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element. J. Biol. Chem. 283, 2654–2662 (2008).

  161. 161.

    et al. NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia. Leukemia 29, 535–547 (2015).

  162. 162.

    et al. The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat. Immunol. (2016).

  163. 163.

    et al. MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int. Immunol. 22, 583–592 (2010).

  164. 164.

    & B-1 B cell development in the fetus and adult. Immunity 36, 13–21 (2012).

  165. 165.

    et al. Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a. J. Exp. Med. 212, 569–580 (2015).

  166. 166.

    et al. Altered lymphopoiesis and immunodeficiency in miR-142 null mice. Proc. Natl Acad. Sci. USA 125, 3720–3730 (2015).

  167. 167.

    et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J. Exp. Med. 208, 1189–1201 (2011). This study describes how the loss of an anti-inflammatory miRNA can lead to autoimmunity and cancer.

  168. 168.

    et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007). This is one of the first studies to demonstrate the role of an inflammatory miRNA in the germinal centre response.

  169. 169.

    , & miR-155: an ancient regulator of the immune system. Immunol. Rev. 253, 146–157 (2013).

  170. 170.

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

  171. 171.

    , , , & Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12, 517–531 (2012).

  172. 172.

    et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28, 621–629 (2008). This is one of the first studies to demonstrate a role for an inflammatory miRNA in B cell class-switching recombination and somatic hypermutation.

  173. 173.

    et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).

  174. 174.

    et al. miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J. Exp. Med. 205, 2199–2206 (2008).

  175. 175.

    et al. MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production. J. Immunol. 191, 3037–3048 (2013).

  176. 176.

    et al. miR-217 is an oncogene that enhances the germinal center reaction. Blood 124, 229–239 (2014).

  177. 177.

    T-cell development and the CD4-CD8 lineage decision. Nat. Rev. Immunol. 2, 309–322 (2002).

  178. 178.

    & Developmental gene networks: a triathlon on the course to T cell identity. Nat. Rev. Immunol. 14, 529–545 (2014).

  179. 179.

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

  180. 180.

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

  181. 181.

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

  182. 182.

    et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005). References 179 and 180 demonstrate the impact of miRNA deletion on T cell development.

  183. 183.

    et al. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150. Blood 117, 7053–7062 (2011).

  184. 184.

    et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007). This interesting study demonstrates how a miRNA can serve as a rheostat for signalling.

  185. 185.

    & Th17 cell differentiation: the long and winding road. Immunity 28, 445–453 (2008).

  186. 186.

    et al. MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J. Immunol. 190, 5972–5980 (2013).

  187. 187.

    et al. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7, e46082 (2012).

  188. 188.

    et al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J. Clin. Invest. 125, 1069–1080 (2015).

  189. 189.

    et al. MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc. Natl Acad. Sci. USA 109, E1248–E1257 (2012).

  190. 190.

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

  191. 191.

    et al. miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORγt and STAT3. J. Immunol. 192, 5599–5609 (2014).

  192. 192.

    et al. Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc. Natl Acad. Sci. USA 110, 11964–11969 (2013).

  193. 193.

    & An allelic series of miR-17 approximately 92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron. Nat. Genet. 47, 766–775 (2015).

  194. 194.

    et al. Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 118, 5487–5497 (2011).

  195. 195.

    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).

  196. 196.

    , , & Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten. J. Immunol. 185, 990–997 (2010).

  197. 197.

    et al. miR-23 approximately 27 approximately 24 clusters control effector T cell differentiation and function. J. Exp. Med. 213, 235–249 (2016).

  198. 198.

    et al. MicroRNAs 24 and 27 suppress allergic inflammation and target a network of regulators of T helper 2 cell-associated cytokine production. Immunity (2016).

  199. 199.

    et al. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41, 605–619 (2014).

  200. 200.

    et al. Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep. 2, 1697–1709 (2012).

  201. 201.

    et al. miR-146a controls the resolution of T cell responses in mice. J. Exp. Med. 209, 1655–1670 (2012).

  202. 202.

    et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914–929 (2010). This is one of the first papers describing the role of miRNAs in Treg cell function.

  203. 203.

    et al. MicroRNAs of the miR-17 approximately 92 family are critical regulators of TFH differentiation. Nat. Immunol. 14, 849–857 (2013).

  204. 204.

    & MicroRNA signatures in human cancers. Nature reviews. Cancer 6, 857–866 (2006).

  205. 205.

    et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).

  206. 206.

    et al. MicroRNA profiling can classify acute leukemias of ambiguous lineage as either acute myeloid leukemia or acute lymphoid leukemia. Clin. Cancer Res. 19, 2187–2196 (2013).

  207. 207.

    et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

  208. 208.

    , & MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 26, 1–12 (2012).

  209. 209.

    et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111, 3183–3189 (2008).

  210. 210.

    & MicroRNA regulation of lymphocyte tolerance and autoimmunity. J. Clin. Invest. 125, 2242–2249 (2015).

  211. 211.

    et al. The role of miRNA in inflammation and autoimmunity. Autoimmun. Rev. 12, 1160–1165 (2013).

  212. 212.

    , , & MicroRNA miR-125b causes leukemia. Proc. Natl Acad. Sci. USA 107, 21558–21563 (2010).

  213. 213.

    et al. Emu/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia 25, 1849–1856 (2011).

  214. 214.

    et al. MicroRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas. Proc. Natl Acad. Sci. USA 111, 8185–8190 (2014).

  215. 215.

    et al. B-cell malignancies in microRNA Emu-miR-1792 transgenic mice. Proc. Natl Acad. Sci. USA 110, 18208–18213 (2013).

  216. 216.

    et al. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Cancer Res. 70, 3833–3842 (2010).

  217. 217.

    et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

  218. 218.

    et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008). This is the first study to demonstrate that aberrant miRNA expression can lead to autoimmune disease.

  219. 219.

    et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J. Exp. Med. 210, 1545–1557 (2013).

  220. 220.

    , & An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).

  221. 221.

    et al. STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-κB to IL-6 signaling axis and STAT3-driven cancer phenotypes. Sci. Signal. 7, ra11 (2014).

  222. 222.

    et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).

  223. 223.

    et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc. Natl Acad. Sci. USA 108, 11193–11198 (2011).

  224. 224.

    et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl Acad. Sci. USA 111, 14888–14893 (2014).

  225. 225.

    , & in vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv. Drug Delivery Rev. 81, 128–141 (2015).

  226. 226.

    et al. Treatment of HCV infection by targeting microRNA. New Engl. J. Med. 368, 1685–1694 (2013).

  227. 227.

    & Therapeutic targeting of microRNAs: current status and future challenges. Nat. Rev. Drug Discov. 13, 622–638 (2014).

  228. 228.

    , & MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat. Rev. Drug Discov. 12, 847–865 (2013).

  229. 229.

    et al. TALEN-based knockout library for human microRNAs. Nat. Struct. Mol. Biol. 20, 1458–1464 (2013).

  230. 230.

    et al. A TALEN-based strategy for efficient bi-allelic miRNA ablation in human cells. RNA 20, 948–955 (2014).

  231. 231.

    , , , & Targeting human microRNA genes using engineered Tal-effector nucleases (TALENs). PLoS ONE 8, e63074 (2013). This paper describes an approach to genetic deletion of miRNAs in human cells using TALENs.

  232. 232.

    et al. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res. 43, e17 (2015).

  233. 233.

    et al. Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system. Scientif. Rep. 4, 3943 (2014).

  234. 234.

    , , & Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009). This study describes a high-throughput approach to identify miRNA targets by looking directly at the binding of miRNAs to mRNAs.

  235. 235.

    , , & Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

  236. 236.

    , , & Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).

  237. 237.

    & Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

  238. 238.

    & MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522–531 (2004).

  239. 239.

    , , & Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, , (2015). This paper describes the algorithm used by Targetscan, a popular miRNA target prediction software.

  240. 240.

    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).

  241. 241.

    et al. Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212. J. Immunol. 190, 1250–1263 (2013).

  242. 242.

    , , & SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008). This study demonstrates that extracellular signalling through growth factors can alter miRNA processing.

  243. 243.

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

  244. 244.

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

  245. 245.

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

  246. 246.

    , & MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 30, 460–471 (2008).

  247. 247.

    , , , & MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl Acad. Sci. USA 105, 1608–1613 (2008).

  248. 248.

    , & Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007).

  249. 249.

    & microRNAs and RNA-binding proteins: a complex network of interactions and reciprocal regulations in cancer. RNA Biol. 10, 935–942 (2013).

  250. 250.

    et al. Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs. Cell 151, 521–532 (2012).

  251. 251.

    , , , & Molecular basis for interaction of let-7 microRNAs with Lin28. Cell 147, 1080–1091 (2011).

  252. 252.

    , & MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat. Rev. Cancer 11, 644–656 (2011).

  253. 253.

    MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat. Rev. Genet. 13, 271–282 (2012).

  254. 254.

    , , , & A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).

  255. 255.

    , & The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014).

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Acknowledgements

The preparation of this review was supported by the US National Institute of Health (RO1AI079243 to D.B.), the National Research Service Award (CA183220 to A.M.) and the University of California, Los Angeles/California Institute of Technology Medical Scientist Training Program (A.M.). The authors also thank J. Zhao, D. Rao and M. Mann for their comments in preparation of this manuscript.

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Affiliations

  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 90025, USA.

    • Arnav Mehta
    •  & David Baltimore
  2. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.

    • Arnav Mehta

Authors

  1. Search for Arnav Mehta in:

  2. Search for David Baltimore in:

Corresponding authors

Correspondence to Arnav Mehta or David Baltimore.

Glossary

Haematopoiesis

The physiological process of creating immune cells in our body.

Long-term haematopoietic stem cell

(LT-HSC). A cell from which all other immune cells originate and that has the unique ability to self-renew.

Multipotent progenitors

(MPPs). Early haematopoietic progenitors that can differentiate into all mature immune cell types but do not have the ability to self-renew.

Autophagy

A normal physiological process through which the cell degrades unnecessary cellular components.

3′ untranslated region

(3′ UTR). The sequence of an mRNA that is downstream of the stop codon.

Robustness

The resilience of different cellular functions to perturbations from extracellular insults.

Protein expression noise

The intrinsic variation in translation that results in different protein expression levels with the same mRNA input.

Bistable switch

A network motif in which there is a binary outcome of either expression of one gene or another.

Microprocessor complex

The complex of two enzymes, Drosha and DGCR8, that cleave pri-miRNAs to pre-mRNAs.

Buffering protein expression

Maintaining the expression of a protein to within a narrowly defined range.

Master regulator

A regulatory element that is essential for the regulation of a developmental process.

Competing endogenous RNAs

(ceRNA). RNAs that bind microRNAs and prevent them from interacting with functionally relevant mRNA targets.

Polycistron

A collection of microRNAs that are expressed in a single transcriptional unit.

miRNA sponge

(microRNA sponge). A transcript with several miRNA-binding sites that is used to downregulate the functional response of a miRNA.

Exhaustion

A state of cellular dysfunction or loss that occurs after aberrant activation and proliferation of a cell.

Rheostat

A gene that allows, through its cellular function, for graded, quantitative control of a biological process, such as cell signalling.

B1 B cells

A subset of B cells expressing high levels of IgM that secrete low-affinity, broad specificity antibodies.

Germinal centre

Sites within lymph nodes, the spleen and other secondary lymphoid organs where mature B cells proliferate and undergo class-switch recombination and somatic hypermutation.

Class-switch recombination

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

B2 B cells

Conventional B cells that secrete highly specific high-affinity antibodies.

Activation-induced deaminase

(AID). An RNA-editing enzyme that is essential for class-switch recombination and somatic hypermutation.

Somatic hypermutation

(SHM). The somatic process by which the antibody repertoire of an activated B cell is mutated to achieve much higher specificity, which is then required for B cell proliferation and survival in the germinal centre.

Double negative 1

(DN1). An early developmental stage of T cell progenitors in the thymus that do not express either CD4 or CD8.

Double positive

(DP). A late developmental stage of T cell progenitors in the thymus that express both CD4 and CD8 on their surface.

Oncomirs

MicroRNAs that lead to cancerous transformation when overexpressed.

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DOI

https://doi.org/10.1038/nri.2016.40

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