Assistant Professor, Pathology and Laboratory Medicine
CIHR New Investigator
Regulation of immunity and inflammation in the gastrointestinal tract
The current research interests of the lab are focused on defining the molecular and cellular mechanisms that regulate immunity and inflammation at mucosal sites. Specifically, I am working with two gastrointestinal (GI) pathogens, the nematode parasite Trichuris muris and the bacterial pathogen Citrobacter rodentium. These two mucosal pathogens provide unique and powerful tools to dissect the regulatory pathways that govern innate and adaptive immune responses in the gut.
Trichurismuris is a natural GI nematode parasite of mice and provides and immunologically well-defined murine model for human trichuriasis, a disease afflicting approximately 1 billion people worldwide. Infective eggs are ingested orally, releasing larval parasites that reside within syncitial epithelial tunnels in the cecum and large intestine. Chronic infection is promoted by type 1 cytokines such as IL-18 and IFN-g, while type 2 cytokines including IL-4, IL-13 and IL-25 mediate host resistance.
Citrobacter rodentium is a natural Gram-negative bacterial pathogen of mice. Citrobacter enters the host orally, colonizes primarily the cecum and distal colon, and results in attaching/effacing lesions, similar to those observed following infection with enteropathogenic Escherichia coli (EPEC). Infection also results in crypt hyperplasia and goblet cell depletion. Resistance to Citrobacter infection has recently been shown to be associated with production of IL-23 and IL-17.
While the basic immunological mechanisms associated with immunity to Trichuris and Citrobacter are becoming clearer, the cellular and molecular mechanisms that control how these pathogens are recognized by the innate immune system, how CD4+ T cell memory is regulated in the gut, how CD4+ T cells migrate to the large intestine and what the immune effector mechanisms are that mediate expulsion of these infections are unknown.
There are four key research areas in the lab:
1. How do intestinal epithelial cells (IECs) regulate innate and adaptive immunity against enteric pathogens? At mucosal sites, IECs are the primary interface that encounters commensal bacteria, food antigens and pathogens. Despite this, there has been little investigation of their role in regulating innate and adaptive responses at mucosal sites. Recently we showed that IEC-intrinsic IkB kinase (IKK)-b-dependent gene expression is a critical regulator of dendritic cell and CD4+ T cell responses in the GI tract (Zaph et al. Nature 446:552, 2007). Ongoing studies are now addressing how IECs regulate CD4+ T cell responses in the gut.
2. When and where do memory CD4+ T cells develop following infection in the gastrointestinal tract? Using a combination of cytokine reporter mice, adoptive transfers and parabiosis, we are defining when and where pathogen-specific memory CD4+ T cell responses develop and how they are maintained in the gut microenvironment.
3. What factors regulate CD4+ T cell migration to the large intestine? While the factors that regulate the migration of T cells to the small intestine are reasonably well characterized, how T cells migrate to the large intestine is less clear. Using gene deficient mice and specific inhibitors of chemokine/ chemokine receptor interactions, we are beginning to elucidate the molecular requirements for CD4+ T cell homing to the large intestine.
4. What is the role of retinoic acid (RA) in the development of intestinal immune responses? RA is a vitamin A metabolite that plays a critical role in embryogenesis and bone and cartilage development. However, there is considerable evidence for a relationship between RA, CD4+ T cell differentiation and acquisition of gut-homing molecules. However, whether RA is required for the development of protective effector and memory CD4+ T cells and immunity to enteric pathogens is unknown.
The long-term goals of my research are to develop an integrated model of how innate and adaptive immune responses in the GI tract are orchestrated, and how future immunological intervention strategies can better manipulate potentially protective and pathologic mucosal responses. The results of these studies will have broad implications for understanding the basic mechanisms that regulate immunity and inflammation at mucosal sites, including dysregulated responses such as inflammatory bowel disease.
Lehnertz, B., Northrop, J.P., Antignano, F., Burrows, K., Hadidi, S., Mullaly, S.C., Rossi, F.M.V. and Zaph, C. 2010. Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J. Exp. Med. In press.
Naus, S.*, Blanchet, M.R.*, Gossens, K., Zaph, C., Bartsch, J.W., McNagny, K.M. and Ziltener, H.J. 2010. The Metalloprotease-Disintegrin ADAM8 is Essential for the Development of Experimental Asthma. Am. J. Respir. Crit. Care. March 1. doi:10.1164/rccm.200909-1396OC
Perrigoue, J.G., Zaph, C., Du, Y., Nair, M.G. and Artis, D. 2009. IL-31-IL-31R interactions limit the magnitude of Th2 cytokine-dependent immunity and inflammation following intestinal helminth infection. J. Immunol. In Press.
Perrigoue, J.G., Saenz, S.A., Allenspach, E.A., Taylor, B.C., Giacomin, P.R., Zaph, C., Nair, M.G., Du, Y., Comeau, M.R., Laufer, T.M. and Artis, D. 2008. MHC class II-dependent basophil-CD4+ T cell interactions promote Th2 cytokine-dependent immunity. Nat. Immunol. In Press.
Nair, M.G., Du, Y., Perrigoue, J.G., Zaph, C., Taylor, J.J., Goldschmidt, M., Swain, G.P., Yancopoulos, G.D., Valenzuela, D.M., Murphy, A., Karow, M., Stevens, S., Pearce, E.J. and Artis, D. 2009. Alternatively activated macrophage-derived RELM–α is a negative regulator of type 2 inflammation in the lung. J. Exp. Med. 206 (4): 937–952.
Taylor, B.C., Zaph, C., Troy, A.E., Du, Y., Guild, K.J., Comeau, M.R. and Artis, D. 2009. TSLP regulates peripheral dendritic cell and T helper cell responses in murine models of intestinal infection and inflammatory bowel disease. J. Exp. Med. 206 (3): 655–667.
Zaph, C., Du, Y., Kobuley, D.E., Guild, K.J., Taylor, B.C., Perrigoue, J.G., Nair, M.G., Saenz, S.A., Troy, A.E., Yu, Y., Kastelein, R.A. Cua, D.J. and Artis, D. 2008. Commensal-dependent expression of IL-25 regulates the IL-23/IL-17 axis in the intestine. J. Exp. Med. 205 (10): 2191–2198.
Nair, M.G., Guild, K.J., Du, Y., Zaph, C., Yancopoulos, G.D., Valenzuela, D.M., Murphy, A., Stevens, S., Karow, M. and Artis, D. 2008. Goblet Cell-Derived RELMβ Augments CD4+ T Cell Production of IFN-γ and Infection-Induced Intestinal Inflammation. J. Immunol. 181 (7): 4709–4715.
Pakpour, N., Zaph, C. and Scott, P. 2008. The Central Memory CD4+ T cell Population Generated during Leishmania major Infection Requires IL-12 to Produce IFN-γ. J. Immunol. 180 (12): 8299–8305.
Perrigoue, J., Li, J., Zaph, C., Goldschmidt, M., Scott, P., Pearce, E.J., Ghilardi, N. and Artis, D. 2007. IL-31–IL-31R interactions negatively regulate type 2 inflammation in the lung. J. Exp. Med. 204 (3): 481–487.
Zaph, C., Troy, A.E., Taylor, B.C., Berman-Booty, L.D., Guild, K.J., Du, Y., Yost, E.A., Gruber, A.D., May, M.J., Greten, F.R., Eckmann, L., Karin, M. and Artis, D. 2007. Epithelial cell-intrinsic IKKβ expression regulates intestinal immune homeostasis. Nature 446 (7135): 552–556.
Zaph, C., Rook, K.A., Goldschmidt, M., Mohrs, M., Scott, P. and Artis, D. 2006. Persistence and Function of Central and Effector Memory CD4+ T Cells Following Infection with a Gastrointestinal Helminth. J. Immunol. 177 (1): 511–518.
Owyang, A.MZaph, C., Wilson, E.H., Guild, K.J., McClanahan, T., Miller, H.R.P., Cua, D.J., Goldschmidt, M., Hunter, C.A., Kastelein, R.A. and Artis, D. 2006. IL-25 regulates type 2 cytokine-dependent immunity and chronic inflammation in the gastrointestinal tract. J. Exp. Med. 203 (4): 843–849.
Zaph, C., Uzonna, J., Beverley, S.M. and Scott, P. 2004. Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites. Nat. Med. 10 (10): 1104–1110.
Frann Antignano PhD, Postdoctoral Research Fellow
Kyle Burrows, Graduate Academic Assistant
Alistair Chenery, Graduate Research Assistant
Menno Oudhoff PhD, Postdoctoral Research Fellow