FACTORS INVOLVED IN THE DIFFERENTIATION OF TGF-BETA-PRODUCING CELLS FROM NAIVE CD4(-CELLS - IL-4 AND IFN-GAMMA HAVE OPPOSING EFFECTS, WHILETGF-BETA POSITIVELY REGULATES ITS OWN PRODUCTION() T)

TGF-beta has been shown to play a central role in regulating inflammat ory responses; thus, understanding the factors involved in the generat ion of TGF-beta-producing cells could lead to interventions that are u seful in effecting disease progression. In initial studies, the capaci ty of naive CD4(+) T cells from TCR transgenic (Tg) mice to produce TG F-beta following primary and secondary stimulation was assessed. TGF-b eta, IL-4, or IFN-gamma production could not be detected from highly p urified naive CD4+/lymphocyte endothelial cell adhesion molecule (LECA M)-1(high) cells following primary stimulation for 36 h with plate-bou nd anti-CD3, anti-CD28, and IL-2, This population was subsequently use d to study the differentiation of TGF-beta-producing CD4(+) T cells. I n further studies, naive CD4(+)/LECAM-1(high) cells from TCR transgeni c 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 v arious cytokines and/or cytokine antagonists for 5 days, restimulated, and TGF-beta, IL-4, and IFN-gamma production were measured. Priming c onditions favoring high IL-4 production and/or low IFN-gamma productio n greatly enhanced TGF-beta production in secondary cultures. Furtherm ore, 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 stu dies showing that cells from IFN-gamma(-/-) mice produced more TGF-bet a, while cells from IL-4(-/-) mice produced less TGF-beta compared wit h wild-type controls. Finally, the addition of exogenous TGF-beta to p riming cultures significantly enhanced the production of TGF-beta upon restimulation, demonstrating that TGF-beta has a role in self-regulat ing its own production.