Bana Jabri, M.D., Ph.D.

Regulation of Memory/Effector T Cell Mediated Immune Respones in Normal and Diseased Conditions; Interface Between Innate and Adaptive Immunity.

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.

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.

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.

Marketon, M.M., Depaolo, R.W., Debord, K.L., Jabri, B, Schneewind, O.  Type III injection of select immune cells during plague infections. Science, 309:1739-41. 2005.

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.

Fujiya, M., Musch, M.W., Nakagawa, Y., Hu, S., Alverdy, J., Kohgo, Y., Schneewind, O., Jabri, B., Chang, E.B.. Quorum sensing CSF of B.subtilis, through OCTN2 transport, contributes to  intestinal homeostasis. Cell Host and Microbe, 1:299-309, 2007.

Siegel, M., Strnad, P., Watts, R.E., Choi ,K., Jabri, B., Omary, M.B., Khosla, C.. Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS ONE 3(3): e1861 doi:10.1371, 2008.

DePaolo RW, Tang F, Kim I, Han M, Levin N, Ciletti N, Anderson DM, Schneewind O and Bana Jabri. 2008. TLR6 drives differentiation of tolerogenic DC and contributes to LcrV-mediated plague pathogenesis. Cell Host & Microbe, 16:350-61, 2008.

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..  Multiple impacts of HLA-DQ8 b57 polymorphism on the anti-gluten T cell response in celiac disease. Nature, 27;534-8, 2008.

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.

Hanaoka, N., Jabri, B., Dai, Z., Ciszewski, C., Stevens, A.M., Yee, C., Nakakuma, H., Spies, T., Groh, V..  NKG2D initiates caspase-medicated CD3 degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease.  J. of Immunol., 185:5732-42. 2010. PMID: 20926796. PMCID in process.

Abadie V, Sollid LM, Barreiro LB, Jabri B, Integration of genetic and immunological insights into a model of celiac disease pathogenesis.  Annu Rev Immunol. 2011 Apr 23;29:493-525.

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.