CD4(-CELLS FROM MAMMARY TUMOR-BEARING MICE HAVE A DOWN-REGULATED PRODUCTION OF IFN-GAMMA - ROLE OF PHOSPHATIDYL SERINE(), BUT NOT CD8(+), T)

IFN-gamma production is dramatically reduced in T cells from mice bear ing large mammary tumors, This inhibition of IFN-gamma gene expression occurs mostly in CD4(+) T cells, as determined by ELISA and reverse t ranscriptase-PCR, The effects of known mammary tumor factors in normal T cells and its subsets were evaluated, Pretreatment with granulocyte -macrophage CSF resulted in increased IFN-gamma levels by T cells, whi le PGE(2) pretreatment equally decreased the levels of this cytokine i n CD4(+) and CD8(+) T cells from normal mice, Interestingly, phosphati dyl serine (PS) down-regulated the IFN-gamma production of CD4(+), but not that of CD8(+), T cells, Methylation analysis indicated that the CpG dinucleotide in SnaBI site of the IFN-gamma 5' promoter flank regi on was hypermethylated in CD4(+), but not in CD8(+), T cells of large tumor bearers and of normal mice pretreated with PS. Electrophoresis m obility shift assay using an oligonucleotide probe corresponding to th e IFN-gamma promoter core region sequence showed a greatly reduced bin ding of a 90-kDa nuclear protein in CD4(+) T cells from tumor bearers and in those from PS-pretreated normal mice, Since IL-2 production is not affected in either CD4(+) or CD8(+) T cells from tumor bearers, th ese studies indicate that IFN-gamma production can be regulated indepe ndently from that of other type 1 cytokines in vivo, Our data further suggest that PS is involved in IFN-gamma gene down-regulation during m ammary tumorigenesis and contributes to the generalized immunosuppress ion associated with tumor growth.