Beta-catenin signaling mediates CD4 expression on mature CD8+ T cells.
Upon activation, a subset of mature human CD8(+) T cells re-expresses CD4 dimly. This CD4(dim)CD8(bright) T cell population is genuine and enriched in antiviral CD8(+) T cell responses. The signaling pathway that leads to CD4 re-expression on mature CD8(+) T cells is not clear. Given that Wnt/beta-catenin signaling plays a critical role in the transition of CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes, we determined whether beta-catenin mediates CD4 expression on mature CD8(+) T cells. We demonstrate that active beta-catenin expression is 20-fold higher on CD4(dim)CD8(bright) than CD4(-)CD8(+) T cells. Activation of beta-catenin signaling, through LiCl or transfection with a constitutively active construct of beta-catenin, induced CD4 on CD8(+) T cells by approximately 10-fold. Conversely, inhibition of beta-catenin signaling through transfection with a dominant-negative construct for T cell factor-4, a downstream effector of beta-catenin signaling, diminished CD4 expression on CD8(+) T cells by 50% in response to T cell activation. Beta-catenin-mediated induction of CD4 on CD8(+) T cells is transcriptionally regulated, as it induced CD4 mRNA, and T cell factor/lymphoid enhancer factor sites were identified within the human CD4 promoter. Further, beta-catenin expression induced the antiapoptotic factor BcL-xL, suggesting that beta-catenin may mediate protection against activation-induced cell death. Collectively, these data demonstrate that beta-catenin is critical in inducing CD4 expression on mature CD8(+) T cells, suggesting that it is a common pathway for CD4 upregulation among thymocytes and mature CD8(+) T cells.
Schenkel
Jason M
JM
Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
Zloza
Andrew
A
Li
Wei
W
Narasipura
Srinivas D
SD
Al-Harthi
Lena
L
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015704:CD4 Antigens / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C494811:BCL2L1 protein, human; D015704:CD4 Antigens; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051020:bcl-X Protein; D051176:beta Catenin; D018021:Lithium Chloride