title: Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory.
abstract: Immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor CD8 T cells, which rapidly regenerate effector and memory cells during recurrent infection. The identification of factors and pathways involved in CD8 T cell differentiation is of obvious importance to improve vaccination strategies. Here, we show that mice lacking T cell factor 1 (Tcf-1), a nuclear effector of the canonical Wingless/Integration 1 (Wnt) signaling pathway, mount normal effector and effector memory CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV). However, Tcf-1-deficient CD8 T cells are selectively impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection. Tcf-1-deficient mice essentially lack CD8 memory precursor T cells, which is evident already at the peak of the primary response, suggesting that Tcf-1 programs CD8 memory cell fate. The function of Tcf-1 to establish CD8 T cell memory is dependent on the catenin-binding domain in Tcf-1 and requires the Tcf-1 coactivators and Wnt signaling intermediates beta-catenin and gamma-catenin. These findings demonstrate that the canonical Wnt signaling pathway plays an essential role for CD8 central memory T cell differentiation under physiological conditions in vivo. They raise the possibility that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or for therapies designed to promote sustained cytotoxic CD8 T cell responses against tumors.
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Lausanne Branch and University of Lausanne, Epalinges, Switzerland.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Jeannet
authors.forename: Caroline
authors.initials: C
authors.lastname: Boudousquié
authors.forename: Noémie
authors.initials: N
authors.lastname: Gardiol
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.forename: Werner
authors.initials: W
authors.lastname: Held
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000172:deficiency / Q000276:immunology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism; D051185:gamma Catenin / Q000276:immunology / Q000378:metabolism
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D051185:gamma Catenin
references.citation: J Immunol. 2004 Feb 1;172(3):1777-85
references.pmid: 14734761
references.citation: Curr Opin Immunol. 2009 Jun;21(3):291-7
references.pmid: 19497720
references.citation: Immunity. 2007 Aug;27(2):281-95
references.pmid: 17723218
references.citation: Nat Med. 2009 Jul;15(7):808-13
references.pmid: 19525962
references.citation: Blood. 2008 Jan 1;111(1):142-9
references.pmid: 17906078
references.citation: J Virol Methods. 1991 Jun;33(1-2):191-8
references.pmid: 1939506
references.citation: J Exp Med. 2007 Sep 3;204(9):2015-21
references.pmid: 17698591
references.citation: Science. 2003 Apr 11;300(5617):339-42
references.pmid: 12690202
references.citation: Nat Immunol. 2001 May;2(5):415-22
references.pmid: 11323695
references.citation: Genes Dev. 2008 Sep 1;22(17):2308-41
references.pmid: 18765787
references.citation: Nature. 2006 Jun 15;441(7095):890-3
references.pmid: 16778891
references.citation: Eur J Immunol. 2007 Jun;37(6):1502-12
references.pmid: 17492805
references.citation: J Exp Med. 2008 Mar 17;205(3):625-40
references.pmid: 18316415
references.citation: Immunity. 2009 Aug 21;31(2):296-308
references.pmid: 19664941
references.citation: Nature. 1995 Mar 2;374(6517):70-4
references.pmid: 7870176
references.citation: J Immunol. 2010 Feb 1;184(3):1191-9
references.pmid: 20026746
references.citation: Nat Immunol. 2003 Dec;4(12):1177-82
references.pmid: 14608382
references.citation: Annu Rev Immunol. 2007;25:171-92
references.pmid: 17129182
references.citation: J Immunol. 2000 Dec 15;165(12):6833-9
references.pmid: 11120806
references.citation: Nature. 2005 Apr 14;434(7035):843-50
references.pmid: 15829953
references.citation: Nature. 2003 Feb 20;421(6925):852-6
references.pmid: 12594515
references.citation: Eur J Immunol. 2006 Dec;36(12):3146-56
references.pmid: 17125145
references.citation: Semin Immunol. 2009 Apr;21(2):62-8
references.pmid: 19269852
references.citation: J Immunol. 2006 Feb 1;176(3):1439-46
references.pmid: 16424171
references.citation: Nat Immunol. 2006 Dec;7(12):1317-25
references.pmid: 17086188
references.citation: Nat Immunol. 2001 Aug;2(8):691-7
references.pmid: 11477404
references.citation: Nat Rev Immunol. 2009 Sep;9(9):662-8
references.pmid: 19680250
references.citation: Immunity. 2007 Dec;27(6):985-97
references.pmid: 18082432