Top

Published in:

01-04-2011

microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells

Authors: Erik Allen Lykken, Qi-Jing Li

Published in: Immunologic Research | Issue 1-3/2011

Abstract

CD4 T cells are an integral part of adaptive immunity. microRNAs have been identified as fundamental regulators of post-transcriptional programs and to play roles in T lymphocytes’ development, differentiation, and effector functions. To better understand the role of miRNAs in T cells and to identify potential therapeutic tools and targets, we have undertaken studies of miRNAs that modulate or are modulated by T-cell receptor signaling. We identified miR-181a as a key regulator of TCR signaling strength, and hence T-cell development, and the miR-17-92 cluster as an important player in CD4 T cells’ response against antigens. These discoveries, coupled with work by other researchers, reveal the power and importance of miRNA-mediated regulation in T-cell responses and offer new insights into the burgeoning field of immunoregulation.

Davis MM, et al. T cells as a self-referential, sensory organ. Annu Rev Immunol. 2007;25:681–95.PubMedCrossRef

Kane LP, Lin J, Weiss A. Signal transduction by the TCR for antigen. Curr Opin Immunol. 2000;12:242–9.PubMedCrossRef

Vang T, et al. Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol. 2008;26:29–55.PubMedCrossRef

Samelson, L.E.: Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu Rev Immunol 2002; 20: 371-394.

Shaw AS, Filbert EL. Scaffold proteins and immune-cell signalling. Nat Rev Immunol. 2009;9:47–56.PubMedCrossRef

Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.PubMedCrossRef

Chen CZ, Li L, Lodish HF, Bartel DP. microRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–6.PubMedCrossRef

Li QJ, et al. miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection. Cell. 2007;129:147–61.PubMedCrossRef

Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD. microRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9:839–45.PubMedCrossRef

10.

Matsui K, Boniface JJ, Steffner P, Reay PA, Davis MM. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci USA. 1994;91:12862–6.PubMedCrossRef

11.

Davis MM, et al. Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol. 1998;16:523–44.PubMedCrossRef

12.

Holler PD, Kranz DM. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity. 2003;18:255–64.PubMedCrossRef

13.

Holler PD, Kranz DM. T cell receptors: affinities, cross-reactivities, and a conformer model. Mol Immunol. 2004;40:1027–31.PubMedCrossRef

14.

Evavold BD, Allen PM. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science. 1991;252:1308–10.PubMedCrossRef

15.

Evavold BD, Sloan-Lancaster J, Allen PM. Antagonism of superantigen-stimulated helper T-cell clones and hybridomas by altered peptide ligand. Proc Natl Acad Sci USA. 1994;91:2300–4.PubMedCrossRef

16.

Krogsgaard M, et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature. 2005;434:238–43.PubMedCrossRef

17.

Pircher H, Rohrer UH, Moskophidis D, Zinkernagel RM, Hengartner H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature. 1991;351:482–5.PubMedCrossRef

18.

Davey GM, et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J Exp Med. 1998;188:1867–74.PubMedCrossRef

19.

Lucas B, Stefanova I, Yasutomo K, Dautigny N, Germain RN. Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity. 1999;10:367–76.PubMedCrossRef

20.

Curtsinger JM, Lins DC, Mescher MF. CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C-) to TCR/CD8 signaling in response to antigen. J Immunol. 1998;160:3236–43.PubMed

21.

Hogquist KA, et al. T cell receptor antagonist peptides induce positive selection. Cell. 1994;76:17–27.PubMedCrossRef

22.

Kao H, Allen PM. An antagonist peptide mediates positive selection and CD4 lineage commitment of MHC class II-restricted T cells in the absence of CD4. J Exp Med. 2005;201:149–58.PubMedCrossRef

23.

Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM. Direct observation of ligand recognition by T cells. Nature. 2002;419:845–9.PubMedCrossRef

24.

Li QJ, et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat Immunol. 2004;5:791–9.PubMedCrossRef

25.

Purbhoo MA, Irvine DJ, Huppa JB, Davis MM. T cell killing does not require the formation of a stable mature immunological synapse. Nat Immunol. 2004;5:524–30.PubMedCrossRef

26.

Ebert PJ, Ehrlich LI, Davis MM. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity. 2008;29:734–45.PubMedCrossRef

27.

Tarakhovsky A, et al. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science. 1995;269:535–7.PubMedCrossRef

28.

Starr TK, Daniels MA, Lucido MM, Jameson SC, Hogquist KA. Thymocyte sensitivity and supramolecular activation cluster formation are developmentally regulated: a partial role for sialylation. J Immunol. 2003;171:4512–20.PubMed

29.

Zikherman J, et al. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Immunity. 2010;32:342–54.PubMedCrossRef

30.

Wu J, et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 2006;281:11002–10.PubMedCrossRef

31.

Zikherman J, et al. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J Immunol. 2009;182:4093–106.PubMedCrossRef

32.

Koelsch U, Schraven B, Simeoni L. SIT and TRIM determine T cell fate in the thymus. J Immunol. 2008;181:5930–9.PubMed

33.

Theodosiou, A. & Ashworth, A.: MAP kinase phosphatases. Genome Biol 2002; 3: REVIEWS3009.

34.

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. Nat Immunol 2009.

35.

Liu G, Min H, Yue S, Chen CZ. Pre-miRNA loop nucleotides control the distinct activities of mir-181a–1, mir-181c in early T cell development. PLoS One. 2008;3:e3592.PubMedCrossRef

36.

Yamasaki S, et al. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nat Immunol. 2006;7:67–75.PubMedCrossRef

37.

Stefanski HE, Mayerova D, Jameson SC, Hogquist KA. A low affinity TCR ligand restores positive selection of CD8+ T cells in vivo. J Immunol. 2001;166:6602–7.PubMed

38.

Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5:772–82.PubMedCrossRef

39.

Reddy J, et al. Detection of autoreactive myelin proteolipid protein 139–151-specific T cells by using MHC II (IAs) tetramers. J Immunol. 2003;170:870–7.PubMed

40.

Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172:5967–72.PubMed

41.

Goodnow, C.C.: Multistep pathogenesis of autoimmune disease. Cell 2007; 130: 25-35.

42.

Bielekova B, et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J Immunol. 2004;172:3893–904.PubMed

43.

Amrani A, et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature. 2000;406:739–42.PubMedCrossRef

44.

Savage PA, Boniface JJ, Davis MM. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999;10:485–92.PubMedCrossRef

45.

Tian J, Gregori S, Adorini L, Kaufman DL. The frequency of high avidity T cells determines the hierarchy of determinant spreading. J Immunol. 2001;166:7144–50.PubMed

46.

Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol. 2007;25:171–92.PubMedCrossRef

47.

van Leeuwen EM, Sprent J, Surh CD. Generation and maintenance of memory CD4(+) T Cells. Curr Opin Immunol. 2009;21:167–72.PubMedCrossRef

48.

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89.PubMedCrossRef

49.

Curtale G, et al. An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood. 2010;115:265–73.PubMedCrossRef

50.

Lu LF, et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010;142:914–29.PubMedCrossRef

51.

Niimoto T, et al. microRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord. 2010;11:209.PubMedCrossRef

52.

Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA. 2007;104:7080–5.PubMedCrossRef

53.

Almanza G, et al. Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One. 2010;5:e11243.PubMedCrossRef

54.

Rodriguez A, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608–11.PubMedCrossRef

55.

Thai TH, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604–8.PubMedCrossRef

56.

Marson A, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445:931–5.PubMedCrossRef

57.

Zheng Y, et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007;445:936–40.PubMedCrossRef

58.

Lu LF, et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009;30:80–91.PubMedCrossRef

59.

Kohlhaas S, et al. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009;182:2578–82.PubMedCrossRef

60.

Tanzer A, Stadler PF. Molecular evolution of a microRNA cluster. J Mol Biol. 2004;339:327–35.PubMedCrossRef

61.

Ota A, et al. EIdentification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma. Cancer Res. 2004;64:3087–95.PubMedCrossRef

62.

He L, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.PubMedCrossRef

63.

Ventura A, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875–86.PubMedCrossRef

64.

Xiao C, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nat Immunol. 2008;9:405–14.PubMedCrossRef

65.

Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.PubMed

66.

Olive V, Jiang I, He L. Mir-17–92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol. 2010;42:1348–54.PubMedCrossRef

67.

Castellano L, et al. The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA. 2009;106:15732–7.PubMedCrossRef

68.

Li G, Luna C, Qiu J, Epstein DL, Gonzalez P. Alterations in microRNA expression in stress-induced cellular senescence. Mech Ageing Dev. 2009;130:731–41.PubMedCrossRef

69.

Yan HL, et al. Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis. EMBO J. 2009;28:2719–32.PubMedCrossRef

70.

Zhang Y, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell. 2010;39:133–44.PubMedCrossRef

71.

Baek, D. et al.: The impact of microRNAs on protein output. Nature 2008.

72.

Selbach, M. et al.: Widespread changes in protein synthesis induced by microRNAs. Nature 2008.

73.

Chi SW, Zang JB, Mele A, Darnell RB. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature. 2009;460:479–86.PubMed

74.

Krutzfeldt J, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.PubMedCrossRef

75.

Thum, T. et al.: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008.

76.

Kota J, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17.PubMedCrossRef

Title: microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells
Authors: Erik Allen Lykken
Qi-Jing Li
Publication date: 01-04-2011
Publisher: Humana Press Inc
Published in: Immunologic Research / Issue 1-3/2011
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-010-8196-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1-3/2011

Mechanisms by which HIV envelope minimizes immunogenicity

Receptor signaling in immune cell development and function

Immunology at Duke: 2011

T-lymphocyte recovery and function after cord blood transplantation

Prevention of GVHD without losing GVL effect: windows of opportunity

A tale of two TRAPs: LAT and LAB in the regulation of lymphocyte development, activation, and autoimmunity