Constitutive activation of Wnt signaling favors generation of memory CD8 T cells.
T cell factor-1 (TCF-1) and lymphoid enhancer-binding factor 1, the effector transcription factors of the canonical Wnt pathway, are known to be critical for normal thymocyte development. However, it is largely unknown if it has a role in regulating mature T cell activation and T cell-mediated immune responses. In this study, we demonstrate that, like IL-7Ralpha and CD62L, TCF-1 and lymphoid enhancer-binding factor 1 exhibit dynamic expression changes during T cell responses, being highly expressed in naive T cells, downregulated in effector T cells, and upregulated again in memory T cells. Enforced expression of a p45 TCF-1 isoform limited the expansion of Ag-specific CD8 T cells in response to Listeria monocytogenes infection. However, when the p45 transgene was coupled with ectopic expression of stabilized beta-catenin, more Ag-specific memory CD8 T cells were generated, with enhanced ability to produce IL-2. Moreover, these memory CD8 T cells expanded to a larger number of secondary effectors and cleared bacteria faster when the immunized mice were rechallenged with virulent L. monocytogenes. Furthermore, in response to vaccinia virus or lymphocytic choriomeningitis virus infection, more Ag-specific memory CD8 T cells were generated in the presence of p45 and stabilized beta-catenin transgenes. Although activated Wnt signaling also resulted in larger numbers of Ag-specific memory CD4 T cells, their functional attributes and expansion after the secondary infection were not improved. Thus, constitutive activation of the canonical Wnt pathway favors memory CD8 T cell formation during initial immunization, resulting in enhanced immunity upon second encounter with the same pathogen.
Zhao
Dong-Mei
DM
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Yu
Shuyang
S
Zhou
Xinyuan
X
Haring
Jodie S
JS
Held
Werner
W
Badovinac
Vladimir P
VP
Harty
John T
JT
Xue
Hai-Hui
HH
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory / Q000235:genetics*; D008089:Listeria monocytogenes / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D051822:T Cell Transcription Factor 1 / Q000096:biosynthesis / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000382:microbiology / Q000821:virology; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D051176:beta Catenin