title: Regulation of immune responses and tolerance: the microRNA perspective.
abstract: Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNA (miRNA) genes, an abundant class of non-coding RNA genes that produce characteristic approximately 22 nucleotides small RNAs, play important roles in immune cells. In this article, we discuss emerging knowledge regarding the functions of miRNA genes in the immune system. We delve into the roles of miRNAs in regulating signaling strength and threshold, homeostasis, and the dynamics of the immune response and tolerance during normal and pathogenic immunological conditions. We also present observations based on analyzes of miR-181 family genes that indicate the potential functions of primary and/or precursor miRNAs in target recognition and explore the impact of these findings on target identification. Finally, we illustrate that despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses. Tuning miRNA functions in immune cells, through gain- and loss-of-function approaches in mice, may reveal novel approach to restore immune equilibrium from pathogenic conditions, such as autoimmune disease and leukemia, without significant toxicity.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. czchen@stanford.edu
authors.forename: Chang-Zheng
authors.initials: CZ
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Schaffert
authors.forename: Rita
authors.initials: R
authors.lastname: Fragoso
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
mesh_terms: D000818:Animals; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007109:Immunity / Q000235:genetics; D056747:Immunomodulation; D051379:Mice; D035683:MicroRNAs / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18986-91
references.pmid: 16357195
references.citation: PLoS One. 2009 Sep 24;4(9):e7158
references.pmid: 19777054
references.citation: Nat Med. 2012 Oct;18(10):1518-24
references.pmid: 23023500
references.citation: Nat Immunol. 2009 Nov;10(11):1162-9
references.pmid: 19801983
references.citation: Nature. 2003 Dec 18;426(6968):845-9
references.pmid: 14685240
references.citation: Cell. 2007 Oct 5;131(1):146-59
references.pmid: 17923094
references.citation: Annu Rev Pathol. 2008;3:587-613
references.pmid: 18039126
references.citation: Cell. 2009 Jan 9;136(1):26-36
references.pmid: 19135886
references.citation: Nature. 2000 Mar 16;404(6775):293-6
references.pmid: 10749213
references.citation: Cell. 2010 Sep 17;142(6):914-29
references.pmid: 20850013
references.citation: Science. 2004 Oct 8;306(5694):269-71
references.pmid: 15472075
references.citation: Nat Rev Genet. 2004 May;5(5):396-400
references.pmid: 15143321
references.citation: Nat Rev Immunol. 2008 Feb;8(2):120-30
references.pmid: 18204468
references.citation: J Exp Med. 1996 May 1;183(5):2283-91
references.pmid: 8642337
references.citation: Science. 2001 Oct 26;294(5543):862-4
references.pmid: 11679672
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60
references.pmid: 15284443
references.citation: Nature. 2000 Feb 24;403(6772):901-6
references.pmid: 10706289
references.citation: FEBS Lett. 2011 Jul 7;585(13):2100-11
references.pmid: 21477587
references.citation: Nat Genet. 2011 Jun 05;43(7):673-8
references.pmid: 21642990
references.citation: Science. 2007 Apr 27;316(5824):604-8
references.pmid: 17463289
references.citation: Cancer Cell. 2010 Sep 14;18(3):282-93
references.pmid: 20832755
references.citation: Nat Immunol. 2008 Apr;9(4):405-14
references.pmid: 18327259
references.citation: Nat Med. 2008 Oct;14(10):1036-40
references.pmid: 18841144
references.citation: Blood. 2009 Feb 19;113(8):1794-804
references.pmid: 18849488
references.citation: EMBO Mol Med. 2011 Oct;3(10):605-15
references.pmid: 21882343
references.citation: Immunity. 2010 Jun 25;32(6):828-39
references.pmid: 20605486
references.citation: Annu Rev Biochem. 1991;60:631-52
references.pmid: 1715680
references.citation: Science. 2001 Aug 10;293(5532):1146-50
references.pmid: 11498593
references.citation: Nature. 2005 Jun 9;435(7043):828-33
references.pmid: 15944707
references.citation: Science. 2007 Apr 27;316(5824):608-11
references.pmid: 17463290
references.citation: Nature. 2005 Dec 1;438(7068):685-9
references.pmid: 16258535
references.citation: Cell. 2008 Mar 7;132(5):875-86
references.pmid: 18329372
references.citation: Blood. 2006 Jul 1;108(1):305-10
references.pmid: 16507772
references.citation: Mol Cell. 2007 Jun 8;26(5):745-52
references.pmid: 17540599
references.citation: PLoS Genet. 2007 Dec;3(12):e215
references.pmid: 18085825
references.citation: Immunity. 2009 Jan 16;30(1):80-91
references.pmid: 19144316
references.citation: Nat Rev Cancer. 2011 Nov 24;11(12):849-64
references.pmid: 22113163
references.citation: Science. 2001 Oct 26;294(5543):853-8
references.pmid: 11679670
references.citation: Cell. 1993 Dec 3;75(5):843-54
references.pmid: 8252621
references.citation: Nat Rev Cancer. 2008 Apr;8(4):279-87
references.pmid: 18354416
references.citation: Cell. 1993 Dec 3;75(5):855-62
references.pmid: 8252622
references.citation: Dev Cell. 2005 Sep;9(3):403-14
references.pmid: 16139228
references.citation: Annu Rev Immunol. 2010;28:295-320
references.pmid: 20307210
references.citation: Cell. 2012 Mar 16;148(6):1172-87
references.pmid: 22424228
references.citation: Nat Med. 2008 Oct;14(10):1041-5
references.pmid: 18841145
references.citation: Genes Dev. 2010 Aug 1;24(15):1614-9
references.pmid: 20679397
references.citation: J Cell Biol. 2011 Nov 28;195(5):709-20
references.pmid: 22123859
references.citation: Nature. 2011 Jan 20;469(7330):336-42
references.pmid: 21248840
references.citation: Arthritis Res Ther. 2008;10(4):R101
references.pmid: 18759964
references.citation: Mol Cell. 2010 Jun 25;38(6):789-802
references.pmid: 20620952
references.citation: Oncogene. 2007 Oct 15;26(47):6838-49
references.pmid: 17934490
references.citation: Nature. 2007 Nov 8;450(7167):299-303
references.pmid: 18172933
references.citation: J Immunol. 2004 May 1;172(9):5230-9
references.pmid: 15100261
references.citation: Science. 2004 Jan 2;303(5654):83-6
references.pmid: 14657504
references.citation: Blood. 1996 May 15;87(10):4025-39
references.pmid: 8639758
references.citation: J Exp Med. 2011 Jun 6;208(6):1189-201
references.pmid: 21555486
references.citation: Dev Cell. 2010 Apr 20;18(4):510-25
references.pmid: 20412767
references.citation: Science. 2001 Oct 26;294(5543):858-62
references.pmid: 11679671
references.citation: Nature. 2005 Jun 9;435(7043):839-43
references.pmid: 15944709
references.citation: Nature. 2004 Aug 12;430(7001):785-9
references.pmid: 15306811
references.citation: Annu Rev Immunol. 2012;30:295-312
references.pmid: 22224773
references.citation: Immunity. 2008 May;28(5):621-9
references.pmid: 18450484
references.citation: Nature. 1998 Feb 19;391(6669):806-11
references.pmid: 9486653
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Autoimmun Rev. 2012 Jan;11(3):174-9
references.pmid: 21621006
references.citation: Cell. 2010 Apr 2;141(1):129-41
references.pmid: 20371350
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Cell. 2007 Apr 6;129(1):147-61
references.pmid: 17382377
references.citation: J Exp Med. 2006 Oct 2;203(10):2239-45
references.pmid: 16966428
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references.pmid: 12434020
references.citation: RNA Biol. 2011 Nov-Dec;8(6):1115-23
references.pmid: 22142974
references.citation: Development. 2008 Dec;135(24):3989-93
references.pmid: 18987025
references.citation: Nature. 2005 Jul 14;436(7048):214-20
references.pmid: 15951802
references.citation: Nature. 2008 Feb 28;451(7182):1125-9
references.pmid: 18278031
references.citation: Nature. 2003 Sep 25;425(6956):415-9
references.pmid: 14508493
references.citation: Genes Dev. 2001 Oct 15;15(20):2654-9
references.pmid: 11641272
references.citation: Immunity. 2008 May;28(5):630-8
references.pmid: 18455451
references.citation: EMBO J. 2010 Oct 6;29(19):3272-85
references.pmid: 20808284
references.citation: Cell. 2009 Jun 12;137(6):1005-17
references.pmid: 19524505
references.citation: Nature. 2009 Aug 6;460(7256):705-10
references.pmid: 19578358
references.citation: Annu Rev Med. 2009;60:167-79
references.pmid: 19630570
references.citation: PLoS Genet. 2012;8(8):e1002855
references.pmid: 22916024
references.citation: RNA. 2012 Nov;18(11):2041-55
references.pmid: 23019594
references.citation: J Exp Med. 1998 Nov 16;188(10):1867-74
references.pmid: 9815264
references.citation: Immunity. 2010 Oct 29;33(4):607-19
references.pmid: 20888269
references.citation: Nat Med. 2012 Jul;18(7):1077-86
references.pmid: 22660635
references.citation: J Immunol. 2011 Sep 1;187(5):2213-21
references.pmid: 21788439
references.citation: J Exp Med. 2011 Apr 11;208(4):663-75
references.pmid: 21464222
references.citation: Nature. 2007 Jun 28;447(7148):1130-4
references.pmid: 17554337
references.citation: Nat Struct Mol Biol. 2010 Oct;17(10):1169-74
references.pmid: 20924405
references.citation: J Exp Med. 2012 Aug 27;209(9):1655-70
references.pmid: 22891274
references.citation: Methods Enzymol. 2007;427:171-89
references.pmid: 17720485
references.citation: Nature. 2005 Jun 16;435(7044):959-63
references.pmid: 15959515
references.citation: J Biol Chem. 2009 Dec 11;284(50):34590-9
references.pmid: 19840932
references.citation: Biochimie. 2002 Sep;84(9):925-44
references.pmid: 12458085
references.citation: Curr Biol. 2010 Jul 27;20(14):1321-5
references.pmid: 20579881
references.citation: PLoS Genet. 2011 Jun;7(6):e1002128
references.pmid: 21738483
references.citation: Nature. 2010 Sep 2;467(7311):86-90
references.pmid: 20693987
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references.pmid: 16885212
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7024-9
references.pmid: 16641092
references.citation: PLoS One. 2008;3(10):e3592
references.pmid: 18974849
references.citation: Nat Methods. 2007 Sep;4(9):721-6
references.pmid: 17694064
references.citation: Semin Immunol. 2003 Apr;15(2):69-79
references.pmid: 12681943
references.citation: Genes Dev. 2010 Aug 1;24(15):1620-33
references.pmid: 20679398