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The Role of TCR gamma-delta T cells in Celiac Disease By: Nertila Ujkaj Littin Kandoth Sandra Mentor: Dr. Manavalan Columbia University, College of Physicians and Surgeons Celiac disease (CD) •a digestive disease that damages the small intestine and interferes with absorption of nutrients from food. •when people with CD consume gluten, their immune system responds by damaging the small intestine •a genetic disorder •symptoms: diarrhea, weight loss, malnutrition, etc… •diagnosis is done by intestinal biopsy histological grading and presence of serum auto- antibodies. •CD is considered an autoimmune disorder because the body's own immune system causes the damage The Gut Lumen IFN-g & Cytotoxic granules IMMUNOPATHOGENESIS OF CELIAC DISEASE Gluten ? MICA/B NKG2D CD94/NKG2C IEL gd T cell IEL ab T cell INTRAEPITHELIAL SPACE Gliadin Peptide IL-15 IL-15 LAMINA PROPRIA HLA-DQ2 or DQ8 Antigen Presenting Cell LP CD4+ T cell B cell Anti-gliadin and anti-TTG2 antibodies Objective • To determine if the TCR gamma-delta IELs in patients with CD are Regulatory/Suppressor T cells – Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self. – They are characterized by having some of the following markers •Intracellular FOXP3 •TGF-beta •IL-10 •CTLA 4 •GITR Methods • Isolation of Lymphocytes from the Duodenal biopsies of 30 patients with Celiac Disease • Immunostaining for the following extracellular and intracellular markers: – T-Cell markers • CD3 • CD8 • TCR alpha-beta • TCR-gamma-delta – Markers for Regulatory/Suppressor cells: • Intra-cellular FOXP3 • Intracellular TGF-beta • GITR • CTLA-4 • Intra-cellular IL-10 • Flow cytometry- technique for counting, examining and sorting microscopic particles (such as cells) suspended in a stream of fluid http://www.flow-cytometry.de/img/fcm.gif A. Immunohistochemistry B. Flow Cytometry EPITHELIAL CELLS INTRAEPITHELIAL LYMPHOCYTES (IEL) Results Results Results Means (error bars: 95% CI for mean) 45 35 30 25 20 15 10 5 50 % Intracellular TGF-beta expressing cells 40 Means (error bars: 95% CI for mean) 40 30 20 10 0 0 TCR alpha-beta TCR gamma-delta TCR alpha-beta TCR gamma-delta IFN-g & Cytotoxic granules Gliadin MICA/B NKG2D CD94/NKG2C TTG IL-15 IEL ab T cell TGFb IEL gd T cell FOXP3 IL-15 HLA-DQ2/8 Antigen Presenting Cell LP CD4+ T cell B cell Anti-gliadin and anti-TTG2 antibodies Conclusion • The TCR gamma-delta T cells have FOXP3 and secrete TGF-beta and are probably Regulator/ Suppressor T cells Future studies • To prove that TCR gamma delta T cells can suppress the immune response • To determine if CD patients who are on therapy have more suppressor TCR gamma-delta T cells than Active CD patients References • Green, P.H. and B. Jabri, Celiac disease. Annu Rev Med, 2006. 57: p. 207-21. • Shan, L., et al., Structural basis for gluten intolerance in celiac sprue. Science, 2002. 297(5590): p. 2275-9. • Meresse, B., et al., Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity, 2004. 21(3): p. 357-66. • Chen, Y., et al., Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A, 2002. 99(22): p. 14338-43. • Peng, S.L., et al., Propagation and regulation of systemic autoimmunity by gammadelta T cells. J Immunol, 1996. 157(12): p. 5689-98. • Roncador, G., et al., Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol, 2005. 35(6): p. 1681-91. • Manavalan, J.S., et al., Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. Int Immunol, 2004. 16(8): p. 1055-68. Acknowledgements •Dr. Manavalan •Dr. Sat Bhattacharya •Harlem Children Society •Allison •Shannon •Harold •Celiac Disease Center of Columbia University Thank You!!!