title: Differences in the transduction of canonical Wnt signals demarcate effector and memory CD8 T cells with distinct recall proliferation capacity.
abstract: Protection against reinfection is mediated by Ag-specific memory CD8 T cells, which display stem cell-like function. Because canonical Wnt (Wingless/Int1) signals critically regulate renewal versus differentiation of adult stem cells, we evaluated Wnt signal transduction in CD8 T cells during an immune response to acute infection with lymphocytic choriomeningitis virus. Whereas naive CD8 T cells efficiently transduced Wnt signals, at the peak of the primary response to infection only a fraction of effector T cells retained signal transduction and the majority displayed strongly reduced Wnt activity. Reduced Wnt signaling was in part due to the downregulation of Tcf-1, one of the nuclear effectors of the pathway, and coincided with progress toward terminal differentiation. However, the correlation between low and high Wnt levels with short-lived and memory precursor effector cells, respectively, was incomplete. Adoptive transfer studies showed that low and high Wnt signaling did not influence cell survival but that Wnt high effectors yielded memory cells with enhanced proliferative potential and stronger protective capacity. Likewise, following adoptive transfer and rechallenge, memory cells with high Wnt levels displayed increased recall expansion, compared with memory cells with low Wnt signaling, which were preferentially effector-like memory cells, including tissue-resident memory cells. Thus, canonical Wnt signaling identifies CD8 T cells with enhanced proliferative potential in part independent of commonly used cell surface markers to discriminate effector and memory T cell subpopulations. Interventions that maintain Wnt signaling may thus improve the formation of functional CD8 T cell memory during vaccination.
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Caroline
authors.initials: C
authors.lastname: Boudousquié
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Maxime
authors.initials: M
authors.lastname: Danilo
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Laurène
authors.initials: L
authors.lastname: Pousse
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Beena
authors.initials: B
authors.lastname: Jeevan-Raj
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Georgi S
authors.initials: GS
authors.lastname: Angelov
authors.affiliation: Swiss Vaccine Research Institute, Lausanne University Hospital, 1066 Epalinges, Switzerland; and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1066 Epalinges, Switzerland.
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Chennupati
authors.affiliation: Swiss Vaccine Research Institute, Lausanne University Hospital, 1066 Epalinges, Switzerland; and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1066 Epalinges, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zehn
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland; Werner.Held@licr.unil.ch.
authors.forename: Werner
authors.initials: W
authors.lastname: Held
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060466:Axin Protein / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D015536:Down-Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis; D007156:Immunologic Memory / Q000276:immunology; D037181:Lectins, C-Type; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014611:Vaccination; D051153:Wnt Proteins / Q000276:immunology*; D060449:Wnt Signaling Pathway / Q000276:immunology*
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D051153:Wnt Proteins