CD4+, but not CD8+, T cells from mammary tumor-bearing mice have a down-regulated production of IFN-gamma: role of phosphatidyl serine.
IFN-gamma production is dramatically reduced in T cells from mice bearing large mammary tumors. This inhibition of IFN-gamma 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-gamma 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-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 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-gamma 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-gamma production can be regulated independently from that of other type 1 cytokines in vivo. Our data further suggest that PS is involved in IFN-gamma gene down-regulation during mammary tumorigenesis and contributes to the generalized immunosuppression associated with tumor growth.
Cheng
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Department of Microbiology and Immunology, University of Miami School of Medicine, and the Sylvester Cancer Center, FL 33101, USA.
Lopez
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DM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010718:Phosphatidylserines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis
D010718:Phosphatidylserines; D012333:RNA, Messenger; D007371:Interferon-gamma