Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10.
CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.
Larmonier
Nicolas
N
Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, AZ 85724-5073, USA.
Marron
Marilyn
M
Zeng
Yi
Y
Cantrell
Jessica
J
Romanoski
Angela
A
Sepassi
Marjan
M
Thompson
Sylvia
S
Chen
Xinchun
X
Andreansky
Samita
S
Katsanis
Emmanuel
E
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells; D015704:CD4 Antigens / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D007938:Leukemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016044:Fusion Proteins, bcr-abl