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PMID: 22216188 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Activation-induced cytidine deaminase expression in CD4+ T cells is associated with a unique IL-10-producing subset that increases with age.

PloS one ·Vol. 6 ·No. 12 ·2011-00-00 ·Pages e29141

Qin H, Suzuki K, Nakata M, Chikuma S, Izumi N, Huong le T, Maruya M, Fagarasan S, Busslinger M, Honjo T, Nagaoka H

Abstract

Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4(+) T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4(+) and B220(+) cell populations. ExAID B cells remained IgM(+), suggesting that class-switched memory B cells do not accumulate in the spleen. In T cells, AID was expressed in a subset that produced IFN-γ and IL-10 but little IL-4 or IL-17, and showed no evidence of genetic mutation. Interestingly, the endogenous Aicda expression in T cells was enhanced in the absence of B cells, indicating that the process is independent from the germinal center reaction. These results suggest that in addition to its roles in B cells, AID may have previously unappreciated roles in T-cell function or tumorigenesis.

MeSH Terms
Aging/blood Animals CD4-Positive T-Lymphocytes/enzymology,metabolism Cytidine Deaminase/blood,genetics Interleukin-10/biosynthesis Mice Mice, Inbred C57BL RNA, Messenger/genetics Real-Time Polymerase Chain Reaction
Chemicals
RNA, Messenger Interleukin-10 AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Qin Hongyan
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Suzuki Keiichiro
Nakata Mikiyo
Chikuma Shunsuke
Izumi Nakako
Huong Le Thi
Maruya Mikako
Fagarasan Sidonia
Busslinger Meinrad
Honjo Tasuku
Nagaoka Hitoshi
References (63)
63 references, click to expand
  1. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes.
    Nature. 2000 Mar 23;404(6776):402-7 PMID: 10746729
  2. Activation-induced cytidine deaminase (AID) is expressed in normal spermatogenesis but only infrequently in testicular germ cell tumours.
    J Pathol. 2006 Sep;210(1):26-31 PMID: 16783758
  3. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression.
    Cell. 2008 Feb 8;132(3):487-98 PMID: 18267078
  4. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.
    Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4262-7 PMID: 14999097
  5. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming.
    J Biol Chem. 2004 Dec 10;279(50):52353-60 PMID: 15448152
  6. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2).
    Cell. 2000 Sep 1;102(5):565-75 PMID: 11007475
  7. PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia.
    Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15807-12 PMID: 19805226
  8. IgA production without mu or delta chain expression in developing B cells.
    Nat Immunol. 2001 Jul;2(7):625-31 PMID: 11429547
  9. Spontaneous and homeostatic proliferation of CD4 T cells are regulated by different mechanisms.
    J Immunol. 2005 May 15;174(10):6039-44 PMID: 15879097
  10. Cutting edge: TLR2 directly triggers Th1 effector functions.
    J Immunol. 2007 Jun 1;178(11):6715-9 PMID: 17513716
  11. Physiologic activation of T cells via the T cell receptor induces NF-kappa B.
    J Immunol. 1991 Jul 15;147(2):416-20 PMID: 1830061
  12. AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development.
    J Exp Med. 2008 Sep 1;205(9):1949-57 PMID: 18678733
  13. AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching.
    Nature. 2001 Dec 6;414(6864):660-665 PMID: 11740565
  14. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches.
    Science. 2009 Mar 13;323(5920):1488-92 PMID: 19286559
  15. Memory B and memory plasma cells.
    Immunol Rev. 2010 Sep;237(1):117-39 PMID: 20727033
  16. Development in motion: helper T cells at work.
    Cell. 2007 Apr 6;129(1):33-6 PMID: 17418783
  17. Nine lives: plasticity among T helper cell subsets.
    J Exp Med. 2009 Aug 3;206(8):1643-6 PMID: 19635860
  18. AID is required for c-myc/IgH chromosome translocations in vivo.
    Cell. 2004 Aug 20;118(4):431-8 PMID: 15315756
  19. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.
    Nature. 2010 Feb 25;463(7284):1101-5 PMID: 20098412
  20. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
    Nature. 1999 Oct 14;401(6754):708-12 PMID: 10537110
  21. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells.
    J Biol Chem. 1999 Jun 25;274(26):18470-6 PMID: 10373455
  22. AID is required for germinal center-derived lymphomagenesis.
    Nat Genet. 2008 Jan;40(1):108-12 PMID: 18066064
  23. Faithful activation of an extra-bright red fluorescent protein in "knock-in" Cre-reporter mice ideally suited for lineage tracing studies.
    Eur J Immunol. 2007 Jan;37(1):43-53 PMID: 17171761
  24. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose.
    Immunity. 2009 Aug 21;31(2):209-19 PMID: 19646904
  25. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium.
    Nat Med. 2007 Apr;13(4):470-6 PMID: 17401375
  26. Role of AID in tumorigenesis.
    Adv Immunol. 2007;94:245-73 PMID: 17560277
  27. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells.
    Science. 2010 Feb 26;327(5969):1098-102 PMID: 20185720
  28. Preferential localization of IgG memory B cells adjacent to contracted germinal centers.
    Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12192-7 PMID: 20547847
  29. B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers.
    Nat Immunol. 2010 Feb;11(2):148-54 PMID: 19966806
  30. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development.
    Immunity. 2008 Jun;28(6):751-62 PMID: 18538592
  31. AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements.
    J Exp Med. 2007 Nov 26;204(12):2989-3001 PMID: 17998390
  32. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
    Cell. 2000 Sep 1;102(5):553-63 PMID: 11007474
  33. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans.
    Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11554-9 PMID: 21700883
  34. T cell-independent somatic hypermutation in murine B cells with an immature phenotype.
    Immunity. 2004 Feb;20(2):133-44 PMID: 14975236
  35. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.
    EMBO J. 1995 Oct 2;14(19):4641-53 PMID: 7588594
  36. Recent immune status determines the source of antigens that drive homeostatic T cell expansion.
    J Immunol. 2005 Mar 15;174(6):3158-63 PMID: 15749843
  37. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut.
    Immunity. 2008 Aug 15;29(2):261-71 PMID: 18656387
  38. A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.
    Oncogene. 2009 Jan 29;28(4):469-78 PMID: 18997814
  39. The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut.
    Immunity. 2010 Jul 23;33(1):71-83 PMID: 20643338
  40. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.
    J Exp Med. 2007 Feb 19;204(2):285-97 PMID: 17283207
  41. Activation of AID by human T-cell leukemia virus Tax oncoprotein and the possible role of its constitutive expression in ATL genesis.
    Carcinogenesis. 2011 Jan;32(1):110-9 PMID: 20974684
  42. Tissue-specific sensitivity to AID expression in transgenic mouse models.
    Gene. 2006 Aug 1;377:150-8 PMID: 16787714
  43. APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo.
    J Virol. 2010 Jul;84(14):7278-87 PMID: 20463074
  44. Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors.
    Immunity. 2007 Jul;27(1):64-75 PMID: 17658280
  45. Interleukin-10 and the interleukin-10 receptor.
    Annu Rev Immunol. 2001;19:683-765 PMID: 11244051
  46. Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation.
    J Exp Med. 2002 Feb 18;195(4):529-34 PMID: 11854365
  47. Constitutive expression of AID leads to tumorigenesis.
    J Exp Med. 2003 May 5;197(9):1173-81 PMID: 12732658
  48. Molecular mechanism of class switch recombination: linkage with somatic hypermutation.
    Annu Rev Immunol. 2002;20:165-96 PMID: 11861601
  49. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.
    Nature. 1991 Apr 4;350(6317):423-6 PMID: 1901381
  50. Activation-induced cytidine deaminase mediates central tolerance in B cells.
    Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11560-5 PMID: 21700885
  51. Generalized lacZ expression with the ROSA26 Cre reporter strain.
    Nat Genet. 1999 Jan;21(1):70-1 PMID: 9916792
  52. A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression.
    Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4506-11 PMID: 15767564
  53. Visualizing memory phenotype development after in vitro stimulation of CD4(+) T cells.
    Cell Immunol. 1998 Aug 25;188(1):1-11 PMID: 9743552
  54. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
    J Exp Med. 2007 Feb 19;204(2):273-83 PMID: 17283209
  55. Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome.
    J Immunol. 2009 Sep 1;183(5):3237-48 PMID: 19667096
  56. T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells.
    J Immunol. 2007 Mar 15;178(6):3593-601 PMID: 17339456
  57. IMGT/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes.
    Nucleic Acids Res. 2005 Jan 1;33(Database issue):D256-61 PMID: 15608191
  58. Regulation of AID expression in the immune response.
    J Exp Med. 2007 May 14;204(5):1145-56 PMID: 17452520
  59. Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression.
    Int J Cancer. 2008 Dec 15;123(12):2735-40 PMID: 18781563
  60. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora.
    Science. 2002 Nov 15;298(5597):1424-7 PMID: 12434060
  61. Locus-specific somatic hypermutation in germinal centre T cells.
    Nature. 1994 Dec 8;372(6506):556-9 PMID: 7990929
  62. Multiple layers of B cell memory with different effector functions.
    Nat Immunol. 2009 Dec;10(12):1292-9 PMID: 19855380
  63. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45.
    Cell. 2008 Dec 26;135(7):1201-12 PMID: 19109892
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0029141
Published
2011-00-00
Epub
2011-00-28
Pages
e29141
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3247255
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0029141 PMC Full Text View journal details
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