Research Interests
T cell immunology in the GI tract: Treg and Th17 differentiation and responses in antimicrobial defense, inflammation and carcinogenesis
I. Dysregulation of mucosal CD4+ T cell response during GI infection and Inflammation. The mucosal T cell response is impaired during H. pylori infection, which contributes to chronicity of infection and the resulting pathogenicity. The existing response is polarized toward a Th1 response, including the production of interferon-γ, which plays an important role in the inflammatory response. The local development of Th17 cells also contributes to inflammation seen during infection. Despite the Th1 and Th17 responses, activated CD4+ cells fail to clear infection and are generally impaired in proliferation. Our work illustrates that gastric epithelial cells can not only act as antigen presenting cells, activating naïve T cell proliferation, but also contribute to the activated T cell anergy/suppression via expression of co-inhibitory molecules during H. pylori infection. Additionally, we have identified a mechanism of local induction of T regulatory (Treg) cells from naïve T cells through the upregulation of the co-inhibitory molecule PD-L1 on the epithelium. We are investigating the role of the gastric epithelium and subepithelial myofibroblasts in the induction of the Treg phenotype, the balance of Treg/Th17, and the inhibition of the T cell response during H. pylori infection and inflammatory bowel disorder.
II. Chronic Inflammation and Carcinogenesis. Chronic inflammation is recognized as a risk factor for carcinogenesis and plays an important role in gastrointestinal cancers. Carcinogenesis of the epithelium is clearly a complex interaction where the transformation of epithelial cells is fostered by the local immune response of the microenvironment. During GI infection and inflammation, epithelial cells and stromal cells such as subepithelial myofibroblasts release a battery of proinflammatory cytokines and growth factors. When these responses become chronic, increased epithelial cell proliferative signaling and inhibition of tumor suppressor pathways may occur creating an environment conducive to carcinogenesis. We are interested in the production, receptor expression, and signaling of proinflammatory cytokines such as macrophage migration inhibitory factor (MIF), interlekin-6, and interleukin-8 (IL-8) in the GI tract and how they may contribute to carcinogenesis when chronically produced.
Our long term research interests include understanding how the host response contributes to the pathogenesis of H. pylori infection and IBD in GI cancers and how it could be harnessed to provide protection.
Selected Publications
Link to PubMed
Beswick, E.J., D.A. Bland, G. Suarez, C.A. Barrera,
X.J. Fan, and V.E. Reyes. Helicobacter pylori Binds to CD74 on Gastric
Epithelial Cells and Stimulates Interleukin-8 Production. Infect Immun.
73:2736-2743, 2005.
Beswick, E.J., S. Das, I.V. Pinchuk, P. Adegboyega, G.
Suarez, Y. Yamaoka, and V.E. Reyes. Helicobacter pylori Induced IL-8
Production by Gastric Epithelial Cells Up-regulates CD74 Expression. J
Immunol. 175:171-176, 2005.
Beswick, E.J., I.V. Pinchuk, K. Minch, G. Suarez, J.C.
Sierra, Y. Yamaoka, and V.E. Reyes. Helicobacter pylori Urease B
Subunit Binds to CD74 on Gastric Epithelial Cells and Induces NF-κB
Activation and IL-8 Production. Infect Immun. 74:1148-1155, 2006.
Das, S., G. Suarez, E.J. Beswick, J.C. Sierra, and V.
E. Reyes. Expression of B7-H1 on Gastric Epithelial Cells: Its
Potential Role in Regulating T Cells during Helicobacter Pylori
Infection. J Immunol. 176:3000-3009, 2006.
Beswick, E.J., I. V. Pinchuk, J.C. Sierra, G. Suarez,
and V.E. Reyes. Helicobacter pylori CagA-dependent Macrophage Migration
Inhibitory Factor Produced by Gastric Epithelial Cells Binds to CD74
and Stimulates Pro-carcinogenic Events. J Immunol. 176:6794-6801, 2006.
Lu, H., J.Y. Wu, E.J. Beswick, T. Ohno, S. Odenbreit,
R. Haas, V.E. Reyes, M. Kita, D.Y. Graham, and Y. Yamaoka. Funtional
Differences in Helicobacter pylori AlpAB Adhesin Cell Signaling in
Western Versus East Asian Strains. J Biol Chem 282:2642-2654, 2007.
Pinchuk, I.V., E.J. Beswick, J.I. Saada, G. Suarez,
J. Winston, R.C. Mifflin, J.F. Di Mari, D.W. Powell, and V.E. Reyes.
MCP-1 Production by Intestinal Myofibroblasts in Response to
Staphylococcal Enterotoxin A: Relevence to Staphylococcal
Enterotoxigenic Disease. J Immunol. 178:8097-8106, 2007.
Beswick, E.J., I.V. Pinchuk, S. Das, D.W. Powell, and
V.E. Reyes. Expression of the programmed death ligand 1, B7-H1, on
gastric epithelial cells after Helicobacter pylori exposure promotes
development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun. 2007
75: 4334-4341.
Reyes, V.E. and E.J. Beswick. Helicobacter pylori
Neutrophil Activatiing Protein’s Potential as a Tool in Therapeutic
Immune Modulation. Expert Opinion on Therapeutic Targets. 10:1315-20,
2007.
Beswick, E.J. and V.E. Reyes. MIF and IL-8 produced by
gastric epithelial cells during Helicobacter pylori exposure induce
expression and activation of the epidermal growth factor receptor.
Infect Immun 76: 3233-3340, 2008.
Pinchuk, I.V., J.I. Saada, E.J. Beswick, G. Boya,
S.M. Qiu, R.C. Mifflin, G.S. Raju, V.E. Reyes, and D.W. Powell. PD-1
ligand expression by human colonic myofibroblasts/firborblasts
regulates CD4+ T cell activity. Gastroenterology. 135:1228-1237, 2008.
Beswick, E.J. and V.E. Reyes. CD74 is antigen
presentation, inflammation, and cancers of the gastrointestinal tract.
World J Gastroenterol 2009; 15: 2855-2861. PMID: 19533806
