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Cytokine Regulation of Intestinal Intraepithelial Lymphocyte Survival and Intestinal Mesenchymal Stromal Cell Function

by
Yingyu Zhang
M.S. in Pathology, 2003
Fudan University
Shanghai, PR China

Thesis Advisor: Dr. Yufang Shi
Graduate Program of Molecular Genetics, Microbiology & Immunology

RWJMS Research Tower
Room V-10

Friday, July 10, 2009
9:00 am


Abstract

We developed an isolation method of mouse intestinal intraepithelial lymphocytes (iIELs) in Part I. In part II, we compared iIELs survival capability with splenic CD8alpha+ T cells and found iIELs to be more susceptible to cell death, especially CD8alphaalpha+TCRalphabeta+ cells. The effects of major TH cytokines on iIELs survival were studied and IL-4 was found able to support iIELs survival through STAT6 signaling. In addition, we also found that intestinal mesenchymal stromal cells (iMSC) were able to promote iIELs activation and directly supported lamina propria lymphocyte (LPL) survival, which is the major source of IL-4. In part III, the IFNgamma, TNFalpha and IL-17 effects on iMSCs functions were studied and three distinct groups of chemokines were strongly activated by different cytokine combinations. Most interestingly, when the three cytokines were combined together, most of the genes induced by single or double cytokine combinations were inhibited with only a few genes enhanced, among which IL-6, MMP-13 and CX3CL1 are most prominent. These gene products are known to be important in the pathogenesis of inflammatory bowel diseases. Further study of transcription factors regulated by IFgamma, TNFalpha and IL-17 uncovered the importance of NFkappaB early activation in this process and a critical role of the later upregulation of c/EBPbeta. Cell migration analysis showed that activated T cell and healthy bone marrow derived stromal cell migrated towards the supernatants from IFNgamma and TNFalpha treated iMSCs, while further addition of IL-17 inhibited this activity.

We conclude that 1. iIELs, especially CD8alphaalpha+ TCRalphabeta+ cells, are susceptible to spontaneous cell death; 2. IL-4 promotes iIELs survival through STAT-6 signaling; 3. iMSCs promote iIELs responsiveness to activation and enhance LPLs survival; 4. IFNgamma, TNFalpha and IL-17 act concertedly on local iMSCs to induce pro-inflammatory gene expressions.


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