CD28 costimulation augments IL-2 secretion of activated lamina propria T cells by increasing mRNA stability without enhancing IL-2 gene transactivation.
The pathways leading to activation in lamina propria (LP) T cells are different from peripheral T cells. LP T cells exhibit enhanced IL-2 secretion when activated through the CD2 pathway. Coligation of CD28 leads to synergistic enhancement of IL-2 secretion. Previous studies have characterized the CD28 augmentation of TCR-mediated signaling in peripheral blood T cells through transcriptional activation of an IL-2 promoter CD28 response element (CD28RE), along with enhanced mRNA stability. This study characterized molecular events involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC). LPMC exhibited increased IL-2 production in response to CD28 costimulation, compared with cells activated through CD2 alone. IL-2 secretion was paralleled by increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability. In contrast to transcriptional activation in PBMC, EMSA revealed that CD28 coligation of CD2-activated LPMC does not result in increased binding of trans-factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I-kappaBbeta levels following CD28 coligation. Furthermore, CD28 coligation fails to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated LPMC. The results reported herein indicate that the molecular mechanisms involved in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to that compartment and differ from those seen in peripheral blood T cells. These observations suggest a biological significance for different mechanisms of IL-2 activation in initiation and maintenance of the cytokine repertoire found in the mucosa.
Gonsky
R
R
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Deem
R L
RL
Lee
D H
DH
Chen
A
A
Targan
S R
SR
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018801:CD2 Antigens / Q000502:physiology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000138:chemical synthesis; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology*
D000276:Adjuvants, Immunologic; D018801:CD2 Antigens; D018106:CD28 Antigens; D007376:Interleukin-2; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1