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

Perera L., Shao, L., Patel, A., Evans, K., Meresse, B., Blumberg, R., Geraghty, D., Groh, V., Spies, T., Jabri, B., Mayer, L. Expression of nonclassical class I molecules by intestinal epithelial cells. Inflamm Bowel Dis. 19:298-307, 2007.

Jabri, B., Ebert, E.  Human CD8 intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunol Rev. 215:202-14, 2007.

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.

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.

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.

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.