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. (1999). Selection and expansion of CD8alpha/alpha(1) T cell receptor alpha/beta(1) intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules.. J Exp Med, 190:885-90.

Jabri B, de Serre NP, Cellier C, Evans K, Gache C, Carvalho C, Mougenot JF, Allez M, Jian R, Desreumaux P, Colombel JF, Matuchansky C, Cugnenc H, Lopez-Botet M, Vivier E, Moretta A, Roberts AI, Ebert EC, Guy-Grand D, Brousse N, Schmitz J, Cerf-Bensussan N. (2000). Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology, 118:867-879.

Roberts AI, Lee L, Schwarz E, Groh V, Spies T, Ebert EC, Jabri B. (2001). Cutting Edge: NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol, 167:5527-30.

Jabri B, Selby JM, Negulescu H, Lee L, Roberts AI, Beavis A, Lopez-Botet M, Ebert EC, Winchester RJ. (2002). TCR Specificity Dictates CD94/NKG2A Expression by Human CTL. Immunity, 17:487-499.

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

Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhaget G, Krausz TN, Raulet DH, Lanier R, Groh V, Spies T, Ebert EC, Green PH, Jabri B. (2004). 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.

Johnson TC, Diamond B, Memeo L, Negulescu H, Hovhanissyan Z, Verkarre V, Rotterdam H, Fasano A, Caillat Zucman S, Grosdidier E, Winchester RJ, Cellier C, Jabri B, Green PH. (2004). Relationship of HLA-DQ8 and Severity Of Celiac disease: Comparison of New York and Parisian Cohorts. Clinical Gastroenterology and Hepatology, 2:888-894.

Jabri B, Kasarda DD, Green PHR. (2005). Celiac Disease. Immunol Rev. 206:219-31.

Sollid LM and Jabri B. (2005). Is celiac disease and autoimmune disease? Curr Opin Immunol. 17:1-6.

Marketon MM, Depaolo W, Debord KL, Jabri B, Schneewind O. (2005). Plaque bacteria target immune cells during infection. Science, 309:1739-41.

Overheim KA, Depaolo RW, Debord KL, Morrin EM, Green NM, Anderson D, Brubaker RR, Jabri B, Schneewind O. (2005). Plague vaccines lacking the immune modulatory properties of rLcrV. Infection and Immunity, 73:5152-5129.

Jabri B and Meresse B. (2006). NKG2 receptor-mediated regulation of effector CTL functions in the human tissue microenvironment. Curr Top Microbiol Immunol 298:139-156.

Green PH, Jabri B. (2006). Celiac Disease. Ann Rev Med. 57:207-21.

Meresse B, Curran SA, Ciszewski C, Orbelyan G, Setty M, Bhagat G, Lee L, Tretiaova M, Semrad C, Kistner E, Winchester RJ, Braud V, Lanier LL, Geraghty D, Green PH, Guandalini S and Jabri B. (2006).  Reprogramming of CTLs into natural killer–like cells in celiac disease.  Journal of Experimental Medicine, 203:1345-55.