The Faculty

Focus

Triggers of celiac disease and immune disorders

Education

Ph.D., Universite Paris, VII, 1996

M.D., Institut Pasteur, Paris, 1991

BPHYS Student

Vu Quoc Dinh

Research Summary

To face multiple environmental aggressions from pathogens and dietary elements, the intestinal mucosa is colonized by an army of mobile antigen-specific effector T lymphocytes and by a distinct population of resident T cells involved in the tissue stress response. The intestine is in fact the only mammalian site allowing ready access to the effector phase of immune responses in the tissue microenvironment.

We study a family of surface receptors called NKG2 that are differentially expressed by subsets of intestinal T cells and regulate the signaling threshold of the T cell antigen receptor through the recruitment of tyrosine phosphatase and kinase. The NKG2 ligands are MHC-I like molecules induced by intestinal epithelial cells upon stress and inflammation. The NKG2 receptors expressed by T cells are themselves regulated by two opposing cytokines IL-15 and TGF secreted by epithelial cells.

This complex system, which ensures the fine-tuning of immune responses by the tissue environment itself, appears to be dysregulated in autoimmune and cancer conditions. A second line of study in the laboratory focuses on an intestinal disease associated with such a dysregulation of the NKG2 system, celiac disease. Celiac disease is provoked by intestinal exposure to a well known dietary antigen, gliadin, in humans expressing the HLA-DQ2 or DQ8 molecules. Using HLA/gliadin tetramers to physically identify the effector T cells in humans and in humanized mouse models, we are dissecting the sequence of events leading to the destruction of intestinal epithelial cells.

Overall, we use a range of molecular and cellular approaches, including the study of signal transduction, cellular immunology and genetic engineering of mouse models, to study the developmental and functional aspects of immune function in the mouse and human intestine. These studies address basic immunological questions and may lead to novel insights into the mechanisms of inflammatory intestinal diseases.

Additional Interests:  T Cell Regulation

Selected Papers

Park, SH., Guy-Grand, D., Lemonnier, FA., Wang, CR, Bendelac, A., Jabri, B. Selection and expansion of CD8aa+TCRab+ intestinal intraepithelial lymphocytes in the absence of both classical MHC class I and non classical CD1 molecules. J Exp Med; 190:885-890. 1999.

Jabri, B, Selby, J., Negulescu, H., Lee, L., Roberts, A.I., Beavis, A., Lopez-Botet, M., Ebert, EC., Winchester, RJ. TCR specificity dictates CD94/NKG2A expression by human CTL. Immunity; 17:487-499. 2002.

Green, HR, Jabri, B.  Coeliac disease.  Lancet, 362: 383-391. 2003.

Meresse, B., Chen, Z, Ciszewski, C., Tretiakova, M., Bhagat, G., Krausz, T.N., Raulet, D.H., Lanier, L.L., Groh, V., Spies, T., Ebert, E.C., Green, P.H., Jabri, B.  Coordinated inducation by IL-15 of a TCR-independent, NKG2D signaling pathway converts CTLs into natural killer-like, lymphokine activated killer (LAK) cells in celiac disease. Immunity, 21:357-366. 2004.

Meresse, B. Curran, S.A., Ciszewski, C., Orbelyan, G., Setty, M., Bhagat, G., Lee, L., Tretiakova, M., Semrad, C., Kistner, E., Winchester, R.J., Braud, V., Lanier, L.L., Geraghty, D., Green, P.H., Guandalini, S. and Jabri, B.  Reprogramming of CTLs into natural killer–like cells in celiac disease.  Journal of Experimental Medicine, 203:1345-55, 2006. PMCID 2121214

Terrazzano, G., Sica, M., Gianfrani, C., Mazzarell, G., Maurano, F., De Giulio, B., de Saint-Mezard, S., Zanzi, D., Maiuri, L., Londei, M., Jabri, B., Troncone, R., Auricchio, S, Zappacosta, S., Carbone, E. Gliadin Regulates the NK-Dendritic Cell Cross-Talk by HLA-E Surface Stabilization. J Immunol. 179:372-81. 2007.

Bhagat, G., Naiye, A.J., Shah, J.G., Harper, J., Jabri, B., Wang, T.C., Green, P.H., Manavalan, J.S.  Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease.  J. Clin. Invest., 118:281-293, 2008. PMCID 2117760

Hovhannisyan, Z., Angela Weiss, A,, Martin, A., Wiesner, M., Tollefsen, S., Yoshida, K., Ciszewski, C., Curran, SA, Murray, JA, David, CS, Sollid, LM,4, Koning, F., Teyton, L., and Jabri, B..  The role of HLA-DQ8 b57 polymorphism on the anti-gluten T cell response in celiac disease. Nature, 456: 534-538, 2008. PMID 19037317 PMCID in process

Tang, F., Chen, Z., Ciszewski, C., Setty, M., Solus, J., Tretiakova, M., Ebert, E., Han, J., Lin, A., Guandalini, S., Groh, V., Spies, T., Green, P. and Jabri, B.. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via  NKG2D and IL-15.  J Exp. Med., 206: 707-19. 2009. PMID 19237603 PMCID 2699120

Jabri, B., Solid, L.M.  Tissue-mediated Control of Immunopathology in Celiac Disease.  Nat Rev Immunol Dec 9:858-870, 2009. PMID: 19935805 PMCID in process

DePaolo, R.W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J.A., Wang, W., Marietta, E.V., Kasarda, D.D.  Waldmann, T.A., Murray, J.A., Semrad, C., Kupfer, S. Belkaid, Y., Guandalini, S., Jabri. B.. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature, 471:220-224, 2011. PMID: 21307853. PMCID: PMC3076739

Abadie V, Sollid LM,  Barreiro, LB, Jabri, B.  Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Ann Rev Immunol. 29:493-525 2011.

Sperandeo, M., Tosco, A., Izzo, V., Tucci, F., Troncone, R., Auricchio, r., Romanos, J., Trynka, G., Auricchio, S., Jabri, B., Greco, L. Potential Celiac Patients: a Model of Celiac Disease Pathogenesis. PLoS ONE, 23:e21281. 2011. PMID:21917438 PMCID: PMC3132737.

Sollid, L, Jabri, B. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr Opin Immunol 23-732-738, 2011. PMID:21917438 PMCID 3428143

Liu, R.B., Engels, B., Arina, A., Schreiber, K., Hyjek, E., Schletinger, A., Binder, D.C., Butz, E., Krausz, T., Rowley, D.A., Jabri, B., Schreiber, H.  Densely granulated murine NK cells eradicate large solid tumors.  Cancer Res. 72,1964-74, 2012.  PMID:22374983 PMCID in process