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The Role of TCR gamma-delta T cells in Celiac Disease

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)

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The Role of TCR gamma-delta T cells in Celiac Disease

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  1. The Role ofTCR gamma-delta T cells in Celiac Disease By: Nertila Ujkaj Littin Kandoth Sandra Mentor: Dr. Manavalan Columbia University, College of Physicians and Surgeons

  2. 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

  3. The Gut Lumen

  4. IFN-g & Cytotoxic granules MICA/B NKG2D CD94/NKG2C IEL gd T cell IL-15 IL-15 LP CD4+ T cell IMMUNOPATHOGENESIS OF CELIAC DISEASE ? Gluten IEL ab T cell INTRAEPITHELIAL SPACE LAMINA PROPRIA Gliadin Peptide HLA-DQ2 or DQ8 Antigen Presenting Cell B cell Anti-gliadin and anti-TTG2 antibodies

  5. 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

  6. 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

  7. http://www.flow-cytometry.de/img/fcm.gif

  8. A. Immunohistochemistry B. Flow Cytometry EPITHELIAL CELLS INTRAEPITHELIAL LYMPHOCYTES (IEL)

  9. Results

  10. Results

  11. Results

  12. IFN-g & Cytotoxic granules MICA/B NKG2D CD94/NKG2C IEL gd T cell FOXP3 IL-15 TGFb IL-15 LP CD4+ T cell Gliadin IEL ab T cell TTG HLA-DQ2/8 Antigen Presenting Cell B cell Anti-gliadin and anti-TTG2 antibodies

  13. 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

  14. 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.

  15. Acknowledgements Dr. Manavalan Dr. Sat Bhattacharya Harlem Children Society Allison Shannon Harold Celiac Disease Center of Columbia University

  16. Thank You!!!

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