Factors involved in the differentiation of TGF-beta-producing cells from naive CD4+ T cells: IL-4 and IFN-gamma have opposing effects, while TGF-beta positively regulates its own production.
TGF-beta has been shown to play a central role in regulating inflammatory responses; thus, understanding the factors involved in the generation of TGF-beta-producing cells could lead to interventions that are useful in effecting disease progression. In initial studies, the capacity of naive CD4+ T cells from TCR transgenic (Tg) mice to produce TGF-beta following primary and secondary stimulation was assessed. TGF-beta, IL-4, or IFN-gamma production could not be detected from highly purified naive CD4+/lymphocyte endothelial cell adhesion molecule (LECAM)-1high cells following primary stimulation for 36 h with plate-bound anti-CD3, anti-CD28, and IL-2. This population was subsequently used to study the differentiation of TGF-beta-producing CD4+ T cells. In further studies, naive CD4+/LECAM-1high cells from TCR transgenic mice of both the BALB/c and B10.A backgrounds were stimulated with T-depleted spleen cells (TDS) and specific peptide in the presence of various cytokines and/or cytokine antagonists for 5 days, restimulated, and TGF-beta, IL-4, and IFN-gamma production were measured. Priming conditions favoring high IL-4 production and/or low IFN-gamma production greatly enhanced TGF-beta production in secondary cultures. Furthermore, the presence of IL-10 in cultures was associated with an increase in TGF-beta production following restimulation. The importance of IL-4 and IFN-gamma in regulating TGF-beta production was confirmed in studies showing that cells from IFN-gamma(-/-) mice produced more TGF-beta, while cells from IL-4(-/-) mice produced less TGF-beta compared with wild-type controls. Finally, the addition of exogenous TGF-beta to priming cultures significantly enhanced the production of TGF-beta upon restimulation, demonstrating that TGF-beta has a role in self-regulating its own production.
Seder
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RA
Lymphokine Regulation Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rseder@nih.gov
Marth
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T
Sieve
M C
MC
Strober
W
W
Letterio
J J
JJ
Roberts
A B
AB
Kelsall
B
B
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D019041:L-Selectin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology
D016212:Transforming Growth Factor beta; D019041:L-Selectin; D015847:Interleukin-4; D007371:Interferon-gamma