title: Wnt signaling inhibits CTL memory programming.
abstract: Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742 USA. Electronic address: xiao0028@umd.edu.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Xiao
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Sun
authors.forename: Kendra
authors.initials: K
authors.lastname: Smyth
authors.forename: Lei
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D007166:Immunosuppressive Agents; D011743:Pyrimidines; D011758:Pyrroles; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C547688:TWS 119; D019041:L-Selectin; D018664:Interleukin-12; D007371:Interferon-gamma; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus
keywords: Cytokines; Cytotoxicity; GSK3; Memory; Rapamycin; T cells; Wnt; mTOR
references.citation: J Immunol. 2005 Oct 1;175(7):4392-9
references.pmid: 16177080
references.citation: Sci Transl Med. 2009 Dec 16;1(11):11ps12
references.pmid: 20371454
references.citation: Annu Rev Immunol. 2005;23:515-48
references.pmid: 15771580
references.citation: J Exp Med. 2003 May 5;197(9):1141-51
references.pmid: 12732656
references.citation: Nat Chem Biol. 2009 Feb;5(2):100-7
references.pmid: 19125156
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: Rev Diabet Stud. 2009;6(2):97-103
references.pmid: 19806239
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: J Immunol. 1999 Mar 15;162(6):3256-62
references.pmid: 10092777
references.citation: Int Immunol. 2007 Jul;19(7):813-24
references.pmid: 17606980
references.citation: Immunity. 2010 Apr 23;32(4):504-6
references.pmid: 20412762
references.citation: Nat Rev Immunol. 2008 Feb;8(2):107-19
references.pmid: 18219309
references.citation: Diabetes. 2009 May;58(5):1156-64
references.pmid: 19208910
references.citation: Cell. 2006 Sep 8;126(5):955-68
references.pmid: 16959574
references.citation: Immunol Res. 2010 Jul;47(1-3):45-55
references.pmid: 20082155
references.citation: PLoS One. 2011;6(9):e25177
references.pmid: 21966447
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15016-21
references.pmid: 18809920
references.citation: Curr Opin Immunol. 2010 Jun;22(3):333-40
references.pmid: 20363604
references.citation: Immunol Rev. 2009 May;229(1):114-25
references.pmid: 19426218
references.citation: Cell. 1994 Jan 14;76(1):17-27
references.pmid: 8287475
references.citation: J Biol Chem. 2011 Nov 11;286(45):38980-8
references.pmid: 21949123
references.citation: Nature. 2009 Jul 2;460(7251):108-12
references.pmid: 19543266
references.citation: Adv Immunol. 2008;100:79-124
references.pmid: 19111164
references.citation: Immunity. 2000 Jul;13(1):15-24
references.pmid: 10933391
references.citation: Cancer Res. 2011 Dec 15;71(24):7628-39
references.pmid: 22009536
references.citation: Nat Med. 2010 May;16(5):513-4; author reply 514-5
references.pmid: 20448567
references.citation: Immunity. 2010 Aug 27;33(2):229-40
references.pmid: 20727791
references.citation: J Cell Mol Med. 2005 Apr-Jun;9(2):255-66
references.pmid: 15963248
references.citation: J Immunol. 2010 Apr 15;184(8):4447-54
references.pmid: 20220092
references.citation: J Clin Invest. 2008 Oct;118(10):3390-402
references.pmid: 18802479
references.citation: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9777-82
references.pmid: 20457902
references.citation: J Immunol. 2005 Apr 15;174(8):4465-9
references.pmid: 15814665
references.citation: Nature. 2009 Oct 1;461(7264):614-20
references.pmid: 19759537
references.citation: J Immunol. 2006 Dec 1;177(11):7515-9
references.pmid: 17114419
references.citation: Annu Rev Biophys Biomol Struct. 1992;21:417-39
references.pmid: 1525472
references.citation: J Mol Med (Berl). 2009 Dec;87(12):1173-8
references.pmid: 19693476
references.citation: Nat Immunol. 2005 Dec;6(12):1236-44
references.pmid: 16273099
references.citation: Semin Immunol. 2009 Apr;21(2):92-8
references.pmid: 19269192
references.citation: Nat Med. 2009 Jul;15(7):808-13
references.pmid: 19525962
references.citation: Br J Haematol. 2009 Mar;144(5):796-8
references.pmid: 19036118
references.citation: Ann Neurol. 2009 Aug;66(2):132-41
references.pmid: 19743458
references.citation: Cell Death Differ. 2001 Feb;8(2):182-91
references.pmid: 11313720
references.citation: Immunol Rev. 2006 Jun;211:81-92
references.pmid: 16824119
references.citation: J Immunol. 2003 Nov 15;171(10):5165-71
references.pmid: 14607916
references.citation: Exp Cell Res. 2011 Nov 15;317(19):2748-58
references.pmid: 21884696
references.citation: Nat Rev Immunol. 2004 Aug;4(8):595-602
references.pmid: 15286726
references.citation: Immunity. 2010 Jan 29;32(1):67-78
references.pmid: 20060330
references.citation: J Immunol. 2011 Jan 15;186(2):784-90
references.pmid: 21149602
references.citation: Nat Med. 2008 Feb;14(2):162-9
references.pmid: 18246080
references.citation: J Immunol. 2009 Mar 1;182(5):2786-94
references.pmid: 19234173
references.citation: Immunity. 2009 Dec 18;31(6):859-71
references.pmid: 20064446
references.citation: Circ Res. 2005 Jul 22;97(2):144-51
references.pmid: 15994435
references.citation: Blood. 2006 Dec 15;108(13):4094-101
references.pmid: 16912227
references.citation: J Carcinog. 2011 Mar 17;10:5
references.pmid: 21483657
references.citation: Nat Rev Immunol. 2008 Aug;8(8):581-93
references.pmid: 18617885
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7
references.pmid: 15314234
references.citation: Immunity. 2010 Apr 23;32(4):568-80
references.pmid: 20381385
references.citation: RNA. 2011 Dec;17(12):2222-34
references.pmid: 22020975
references.citation: J Immunol Methods. 1995 Jul 17;184(1):39-51
references.pmid: 7622868
references.citation: Nature. 2009 Jul 2;460(7251):103-7
references.pmid: 19494812
references.citation: J Immunol. 2010 Feb 1;184(3):1191-9
references.pmid: 20026746
references.citation: J Biol Chem. 2001 May 18;276(20):17479-83
references.pmid: 11278246
references.citation: Nature. 2005 Apr 14;434(7035):843-50
references.pmid: 15829953
references.citation: Gastroenterology. 2010 Sep;139(3):869-81, 881.e1-9
references.pmid: 20580720
references.citation: J Immunol. 2006 Feb 1;176(3):1439-46
references.pmid: 16424171
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: Dev Cell. 2007 Dec;13(6):759-60
references.pmid: 18061557
references.citation: Cell Signal. 2012 Apr;24(4):846-51
references.pmid: 22182510
references.citation: Nat Immunol. 2007 Mar;8(3):239-45
references.pmid: 17304234
references.citation: Science. 2002 Jan 11;295(5553):338-42
references.pmid: 11786644
references.citation: Nat Rev Immunol. 2002 Apr;2(4):251-62
references.pmid: 12001996
references.citation: J Biol Chem. 2005 Jan 14;280(2):1037-43
references.pmid: 15522880
references.citation: Gastroenterology. 2010 Sep;139(3):718-22
references.pmid: 20659460
references.citation: J Exp Med. 2005 Sep 5;202(5):637-50
references.pmid: 16129706