Insufficient interleukin-12 signalling favours differentiation of human CD4(+) and CD8(+) T cells into GATA-3(+) and GATA-3(+) T-bet(+) subsets in humanized mice.
Differentiation of CD4(+) T cells into type 1 or type 2 subsets is mediated by the expression of the opposing lineage defining transcription factors T-bet and GATA-3. However, the existence of GATA-3(+) T-bet(+) CD4(+) T cells in mice suggests functional plasticity of these subsets. Little is known about type 1 and type 2 plasticity of human T-cell subsets in vivo. Here, we show that in the xenogeneic environment of humanized mice, which lacks a functional immune-regulatory network, human CD4(+) and, notably, CD8(+) T cells preferentially differentiate into interleukin (IL)-4(+) GATA-3(+) and IL-4(+) interferon-γ(+) GATA-3(+) T-bet(+) subsets. Treatment with recombinant human IL-12 or expansion of IL-12-producing human dendritic cells in vivo reverted this phenotype and led to the down-regulation of GATA-3 expression. These changes also correlated with improved antiviral immune responses in humanized mice. In conclusion, our study shows the capacity of human CD4(+) and CD8(+) T cells for stable co-expression of GATA-3 and T-bet in humanized mice and reveals a critical role for IL-12 in regulating this phenotype.
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA.
Eva
E
Billerbeck
Rachael N
RN
Labitt
Kevin
K
Vega
Natalia
N
Frias-Staheli
Marcus
M
Dorner
Jing W
JW
Xiao
Charles M
CM
Rice
Alexander
A
Ploss
D000256:Adenoviridae / Q000472:pathogenicity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D054884:Host-Pathogen Interactions; D006801:Humans; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D014183:Transplantation, Heterologous; D019562:Viral Load; D000098815:T-bet Transcription Factor
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C573415:IFNG protein, human; C508598:IL4 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma
T-cell plasticity; humanized mice; interleukin-12