Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1.
T cell factor 1 (TCF-1) is a transcription factor known to act downstream of the canonical Wnt pathway and is essential for normal T cell development. However, its physiological roles in mature CD8(+) T cell responses are unknown. Here we showed that TCF-1 deficiency limited proliferation of CD8(+) effector T cells and impaired their differentiation toward a central memory phenotype. Moreover, TCF-1-deficient memory CD8(+) T cells were progressively lost over time, exhibiting reduced expression of the antiapoptotic molecule Bcl-2 and interleukin-2 receptor beta chain and diminished IL-15-driven proliferation. TCF-1 was directly associated with the Eomes allele and the Wnt-TCF-1 pathway was necessary and sufficient for optimal Eomes expression in naive and memory CD8(+) T cells. Importantly, forced expression of Eomes partly protected TCF-1-deficient memory CD8(+) T cells from time-dependent attrition. Our studies thus identify TCF-1 as a critical player in a transcriptional program that regulates memory CD8 differentiation and longevity.
Zhou
Xinyuan
X
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Yu
Shuyang
S
Zhao
Dong-Mei
DM
Harty
John T
JT
Badovinac
Vladimir P
VP
Xue
Hai-Hui
HH
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C491198:Eomes protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D019409:Interleukin-15; D051822:T Cell Transcription Factor 1; D020825:T-Box Domain Proteins; D051153:Wnt Proteins; D051176:beta Catenin