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.

  • Perspective
  • Published:

Short-term memory of danger signals and environmental stimuli in immune cells

Abstract

Standard definitions of immunological memory are all built on the idea that once infected, animals are protected more efficiently against a second infection. This common view overlooks an unavoidable consequence of the exposure of cells to pathogens, danger signals and environmental agents in general: stimuli change cell properties and activity in a transient yet sustained manner that extends beyond the exposure time and modulates the response of cells of both the innate and adaptive immune systems to secondary stimulation. We suggest that this transient phenomenon represents 'short-term memory' of environmental exposure and discuss the evidence that this is mediated by the persistence of long-lived regulatory molecules, notably a subset of newly deposited chromatin modifications and inducible noncoding RNAs.

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

Access options

Buy this article

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

Figure 1: Inducible, long-lasting regulatory molecules are mediators of short-term memory of environmental stimuli.
Figure 2: Potential mechanisms of short-term memory mediated by chromatin modifications and miRNAs.

Similar content being viewed by others

References

  1. Biswas, S.K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. del Fresno, C. et al. Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J. Immunol. 182, 6494–6507 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Limaye, A.P. et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. J. Am. Med. Assoc. 300, 413–422 (2008).

    Article  CAS  Google Scholar 

  4. van der Poll, T. & Opal, S.M. Host-pathogen interactions in sepsis. Lancet Infect. Dis. 8, 32–43 (2008).

    Article  PubMed  CAS  Google Scholar 

  5. Hottiger, M.O., Felzien, L.K. & Nabel, G.J. Modulation of cytokine-induced HIV gene expression by competitive binding of transcription factors to the coactivator p300. EMBO J. 17, 3124–3134 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Hazzalin, C.A. & Mahadevan, L.C. Dynamic acetylation of all lysine 4-methylated histone H3 in the mouse nucleus: analysis at c-fos and c-jun. PLoS Biol. 3, e393 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bernstein, B.E., Meissner, A. & Lander, E.S. The mammalian epigenome. Cell 128, 669–681 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Zee, B.M., Levin, R.S., Dimaggio, P.A. & Garcia, B.A. Global turnover of histone post-translational modifications and variants in human cells. Epigenetics Chromatin 3, 22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zee, B.M. et al. In vivo residue-specific histone methylation dynamics. J. Biol. Chem. 285, 3341–3350 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Ruthenburg, A.J., Allis, C.D. & Wysocka, J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol. Cell 25, 15–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Hargreaves, D.C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Santa, F. et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 28, 3341–3352 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Byun, J.S. et al. Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes. Proc. Natl. Acad. Sci. USA 106, 19286–19291 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Heintzman, N. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boyle, A.P. et al. High-resolution mapping and characterization of open chromatin across the genome. Cell 132, 311–322 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Heintzman, N.D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Article  CAS  Google Scholar 

  23. Neph, S. et al. An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 489, 83–90 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thurman, R.E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Natoli, G. Maintaining cell identity through global control of genomic organization. Immunity 33, 12–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Samstein, R.M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jeong, K.W. et al. Recognition of enhancer element-specific histone methylation by TIP60 in transcriptional activation. Nat. Struct. Mol. Biol. 18, 1358–1365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cloos, P.A., Christensen, J., Agger, K. & Helin, K. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22, 1115–1140 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burgess, R.J. & Zhang, Z. Histone chaperones in nucleosome assembly and human disease. Nat. Struct. Mol. Biol. 20, 14–22 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Elsaesser, S.J., Goldberg, A.D. & Allis, C.D. New functions for an old variant: no substitute for histone H3.3. Curr. Opin. Genet. Dev. 20, 110–117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dion, M.F. et al. Dynamics of replication-independent histone turnover in budding yeast. Science 315, 1405–1408 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Deng, W. et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 149, 1233–1244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cullen, K.E., Kladde, M.P. & Seyfred, M.A. Interaction between transcription regulatory regions of prolactin chromatin. Science 261, 203–206 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. de Wit, E. & de Laat, W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 26, 11–24 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tanay, A. & Cavalli, G. Chromosomal domains: epigenetic contexts and functional implications of genomic compartmentalization. Curr. Opin. Genet. Dev. 23, 197–203 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Gibcus, J.H. & Dekker, J. The hierarchy of the 3D genome. Mol. Cell 49, 773–782 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dixon, J.R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nora, E.P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Tan-Wong, S.M., Wijayatilake, H.D. & Proudfoot, N.J. Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex. Genes Dev. 23, 2610–2624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Deng, W. & Blobel, G.A. Do chromatin loops provide epigenetic gene expression states? Curr. Opin. Genet. Dev. 20, 548–554 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van de Werken, H.J. et al. Robust 4C-seq data analysis to screen for regulatory DNA interactions. Nat. Methods 9, 969–972 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. He, Y.F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S. & Heintz, N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Yildirim, O. et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147, 1498–1510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Valinluck, V. & Sowers, L.C. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 67, 946–950 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Guo, J.U., Su, Y., Zhong, C., Ming, G.L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423–434 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cortellino, S. et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146, 67–79 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Pastor, W.A. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394–397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xu, Y. et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451–464 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, Q., Chen, Y., Bian, C., Fujiki, R. & Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Vella, P. et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49, 645–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Dawlaty, M.M. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu, H. et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25, 679–684 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Spruijt, C.G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and Its oxidized derivatives. Cell 152, 1146–1159 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Dawlaty, M.M. et al. Combined deficiency of tet1 and tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev. Cell 24, 310–323 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ko, M. et al. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc. Natl. Acad. Sci. USA 108, 14566–14571 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Koh, K.P. et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509–4518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cimmino, L., Abdel-Wahab, O., Levine, R.L. & Aifantis, I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9, 193–204 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gu, T.P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Smith, Z.D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Kallin, E.M. et al. Tet2 facilitates the derepression of myeloid target genes during CEBPalpha-induced transdifferentiation of pre-B cells. Mol. Cell 48, 266–276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bruniquel, D. & Schwartz, R.H. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat. Immunol. 4, 235–240 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Kersh, E.N. et al. Rapid demethylation of the IFN-γ gene occurs in memory but not naive CD8 T cells. J. Immunol. 176, 4083–4093 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Rüegger, S. & Grosshans, H. MicroRNA turnover: when, how, and why. Trends Biochem. Sci. 37, 436–446 (2012).

    Article  PubMed  CAS  Google Scholar 

  85. Kai, Z.S. & Pasquinelli, A.E. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat. Struct. Mol. Biol. 17, 5–10 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bhattacharyya, S.N., Habermacher, R., Martine, U., Closs, E.I. & Filipowicz, W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111–1124 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Gatfield, D. et al. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev. 23, 1313–1326 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Park, C.Y. et al. A resource for the conditional ablation of microRNAs in the mouse. Cell Rep 1, 385–391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Leung, A.K. & Sharp, P.A. MicroRNA functions in stress responses. Mol. Cell 40, 205–215 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hutvágner, G. & Zamore, P.D. A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056–2060 (2002).

    Article  PubMed  CAS  Google Scholar 

  92. Baccarini, A. et al. Kinetic analysis reveals the fate of a microRNA following target regulation in mammalian cells. Curr. Biol. 21, 369–376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, X., Liang, H., Zhang, J., Zen, K. & Zhang, C.Y. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 22, 125–132 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Montecalvo, A. et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119, 756–766 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Rusca, N. et al. MiR-146a and NF-κB1 regulate mast cell survival and T lymphocyte differentiation. Mol. Cell Biol. 32, 4432–4444 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Boldin, M.P. et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J. Exp. Med. 208, 1189–1201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhao, J.L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Boldin, M.P. & Baltimore, D. MicroRNAs, new effectors and regulators of NF-κB. Immunol. Rev. 246, 205–220 (2012).

    Article  PubMed  CAS  Google Scholar 

  103. Montagner, S., Orlandi, E.M., Merante, S. & Monticelli, S. The role of miRNAs in mast cells and other innate immune cells. Immunol. Rev. (in the press) (2013).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Zheng, Q., Zhou, L. & Mi, Q.S. MicroRNA miR-150 is involved in Vα14 invariant NKT cell development and function. J. Immunol. 188, 2118–2126 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Mayoral, R.J. et al. MiR-221 influences effector functions and actin cytoskeleton in mast cells. PLoS ONE 6, e26133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rossato, M. et al. IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc. Natl. Acad. Sci. USA 109, E3101–E3110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bezman, N.A., Chakraborty, T., Bender, T. & Lanier, L.L. miR-150 regulates the development of NK and iNKT cells. J. Exp. Med. 208, 2717–2731 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bronevetsky, Y. et al. T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J. Exp. Med. 210, 417–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Diederichs, S. & Haber, D.A. Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell 131, 1097–1108 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. 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  PubMed  PubMed Central  Google Scholar 

  114. Olejniczak, S.H., La Rocca, G., Gruber, J.J. & Thompson, C.B. Long-lived microRNA-Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses. Proc. Natl. Acad. Sci. USA 110, 157–162 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  116. Krol, J. et al. Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell 141, 618–631 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Hansen, T.B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Thomas, M.F. et al. Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function. Blood 120, 130–142 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Guttman, M. & Rinn, J.L. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, K.C. & Chang, H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ponting, C.P., Oliver, P.L. & Reik, W. Evolution and functions of long noncoding RNAs. Cell 136, 629–641 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Willingham, A.T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Sharma, S. et al. Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc. Natl. Acad. Sci. USA 108, 11381–11386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hung, T. et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat. Genet. 43, 621–629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ørom, U.A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46–58 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Gomez, J.A. et al. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152, 743–754 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P.P. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Marangoni, F. et al. The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity 38, 237–249 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank K.M. Ansel for encouragement. Supported by the Swiss National Science Foundation (31003A_138343 for the S.M. laboratory), Novartis Stiftung für Medizinisch Biologische Forschung (S.M. laboratory) and the European Research Council (G.N. laboratory).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Silvia Monticelli or Gioacchino Natoli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Monticelli, S., Natoli, G. Short-term memory of danger signals and environmental stimuli in immune cells. Nat Immunol 14, 777–784 (2013). https://doi.org/10.1038/ni.2636

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2636

This article is cited by

Search

Quick links

Nature Briefing

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

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