CD2 mediates activation of the IFN-gamma intronic STAT binding region in mucosal T cells.
The pathways leading to activation of mucosal lamina propria (LP) T cells differ from those of peripheral T cells. LP T cells exhibit enhanced IFN-gamma secretion when activated through the CD2 pathway. This study demonstrates CD2 signaling is followed by activation of STAT proteins in both peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC), although, distinct differences exist in regulation of IFN-gamma promoter gene expression. Both PBMC and LPMC exhibit enhanced secretion and transactivation of the -2.7 kb IFN-gamma promoter region following CD2 signaling, but the IFN-gamma STAT-binding region (within the first intron) serves as an orientation-independent enhancer of promoter activity only in LPMC. Mutation of the STAT site impairs enhancer activity. In LPMC, but not PBMC, CD2 mediates binding of STAT1 and STAT4 to the IFN-gamma intronic element. Unstimulated LMPC exhibit low levels of phosphotyrosine-STAT4 and STAT1 and phosphoserine-STAT1, which increase substantially following CD2 activation. In PBMC, CD2-mediated phosphorylation is primarily restricted to enhanced levels of phosphotyrosine-STAT1. Thus, these results indicate that both common as well as unique molecular mechanisms are involved in CD2 signaling and activation of the STAT pathway in LP T cells which are critical for regulation of IFN-gamma expression in the gut.
Gonsky
Rivkah
R
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Deem
Richard L
RL
Young
Howard A
HA
Targan
Stephan R
SR
D000818:Animals; D001665:Binding Sites; D018801:CD2 Antigens / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology*; D007438:Introns; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
D018801:CD2 Antigens; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma