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CD4⁺, But Not CD8⁺, T Cells from Mammary Tumor-Bearing Mice Have a Down-Regulated Production of IFN-: Role of Phosphatidyl Serine¹

Department of Microbiology and Immunology, University of Miami School of Medicine, and the Sylvester Cancer Center, Miami, FL 33101

IFN- production is dramatically reduced in T cells from mice bearing large mammary tumors. This inhibition of IFN- gene expression occurs mostly in CD4⁺ T cells, as determined by ELISA and reverse transcriptase-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- levels by T cells, while PGE₂ pretreatment equally decreased the levels of this cytokine in CD4⁺ and CD8⁺ T cells from normal mice. Interestingly, phosphatidyl serine (PS) down-regulated the IFN- production of CD4⁺, but not that of CD8⁺, T cells. Methylation analysis indicated that the CpG dinucleotide in SnaBI site of the IFN- 5' promoter flank region was hypermethylated in CD4⁺, but not in CD8⁺, T cells of large tumor bearers and of normal mice pretreated with PS. Electrophoresis mobility shift assay using an oligonucleotide probe corresponding to the IFN- promoter core region sequence showed a greatly reduced binding 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, these studies indicate that IFN- production can be regulated independently from that of other type 1 cytokines in vivo. Our data further suggest that PS is involved in IFN- gene down-regulation during mammary tumorigenesis and contributes to the generalized immunosuppression associated with tumor growth.

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