DC expressing transgene Foxp3 are regulatory APC.
Tolerogenic DC and suppressive Foxp3(+) Treg play important roles in preventing autoimmunity and allograft rejection. We report that (adenovirus mediated) ectopic expression of Foxp3 in human DC (i.e. DC.Foxp3) yields an APC that severely limits T-cell proliferation and type-1 immune responses from the naïve, but not memory, pool of responder T cells in vitro. In marked contrast, the frequencies of type-2 and Treg responses were dramatically increased after stimulation of naïve T cells with DC.Foxp3 versus control DC. DC.Foxp3-induced CD4(+)CD25(+) Treg cells potently suppressed the proliferation of, and IFN-gamma production from, CD4(+) and CD8(+) responder T cells. Notably, the immunosuppressive biology of DC.Foxp3 was effectively normalized by addition of 1-methyl-tryptophan or neutralizing anti-TGF-beta1 Ab during the period of T-cell priming. These data suggest the potential utility of regulatory DC.Foxp3 and/or DC.Foxp3-induced CD4(+)CD25(+) Treg as translational agents for the amelioration or prevention of pathology in the setting of allograft transplantation and/or autoimmunity.
Lipscomb
Michael W
MW
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Taylor
Jennifer L
JL
Goldbach
Cristina J
CJ
Watkins
Simon C
SC
Wesa
Amy K
AK
Storkus
Walter J
WJ
D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C525121:1-methyl-3-oxo-7-oxabicyclo(2.2.1)hept-5-ene-2-carboxylic acid methyl ester; D057134:Antibodies, Neutralizing; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma