Biographical Sketch:

Undergraduate degree was in preprofessional studies at Notre Dame and medical school degree was from University of Illinois with honors. Internal medicine residency was at Rush Presbyterian St. Luke's in Chicago and gastroenterology fellowship was at the University of Chicago. After fellowship training a three year "post doc" was spent in the Dept. of Pathology / Section of Immunology at the University of Chicago with Jeffrey Bluestone Ph.D. where the project utilized gamma/delta TCR transgenic mice to address questions of self-tolerance in the intestine. Appointment as Assistant Professor at Northwestern began in 1991 in Dept. of Medicine with a coappointment in the Dept. of Microbiology /Immunology in 1993. Appointment to the Integrated Graduate school faculty was finalized in 1995 and since then two graduate students have successfully defended Ph.D. dissertations with two currently working in the lab.

Short Research Description:

Projects focus on questions related to T cell activation in the intestine in normal and abnormal states of inflammation. The lab utilizes the DO11.10 TCR transgenic mouse model in adoptive transfer and mixed bone marrow chimera mice to study the role of oral antigen, costimulation and programmed cell death on mucosal T cell functional differentiation. Effects of intestinal T cell activation in the intestine have focused on the induction of epithelial cell apoptosis and enhanced mucosal permeability. These studies utilize lpr/lpr mutant strains and TNFR-1 double knockout mice to examine the mechanisms involved in crypt epithelial cell apoptosis induced by intestinal T cell activation.

Research Abstract:

We focus on a specific type of effector T cell localized to the extralymphoid tissue of the intestine. At this site CD4+ T cells provide help to local B cells and enhance activities of local macrophages which participate in vital host defenses against enteric bacteria. To address the mechanisms used to create this unique population we have utilized OVA antigen (Ag)-specific DO11.10 TCR transgenic mice. In previous studies (S.D. Hurst et al, PNAS, 1997) these mice were used to demonstrate that enteric antigen (Ag) induces the functional differentiation of intestinal T cells via T cell receptor (TCR) signaling. To address the mechanisms involved in this process we have backcrossed the DO11.10 mice onto the RAG-1-/- background. These mice are then combined with normal BALB/c bone marrow (BM) to generate mixed BM chimera mice which have Ag-specific transgenic T cells in mice with normal numbers of nontransgenic B and T cells. This model is now being used to examine the role of oral antigen, costimulation and programmed cell death in mucosal T cell functional differentiation. It is believed that by understanding mechanisms involved in normal T cell responses in the intestine we will be able to develop novel approaches to the development of new oral vaccines and treatments for inflammatory bowel disease (IBD).

In new studies in the lab we are addressing the mechanisms involved in crypt epithelial cell apoptosis in the intestine. We found that activation of T cells in DO11.10 mice induces a striking apoptosis (programmed cell death) of crypt epithelial cells in the small and large intestine. Along with increased crypt cell apoptosis we found that mucosal permeability to small (sugars) and large (inulin) molecular probes was increased along the same time course. Thus, we suspect that we have a model for the mucosal barrier abnormalities observed in human IBD. We are now focusing on the role of Fas and tumor necrosis factor receptor (TNFR-1) in mediating the apoptosis and the increase in mucosal permeability using mutant and gene knockout mice.

Publications:

Barrett, TA, M Delvy, D Kennedy, L Lefrancois, L Matis, AL Dent, SM Hedrick, JA Bluestone. Mechanism of self-tolerance of T cells in epithelial tissues. J. Exp. Med. 175: 65-70, 1992.

Barrett, TA, Y Tatsumi, JA Bluestone. Tolerance of T cell receptor / IELs. J. Exp. Med. 177:1755-1762, 1993.

Guehler, S, Bluestone, JA and TA Barrett. Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts. J. Exp. Med. 184(2): 493-503, 1996.

Karpus, WJ, Lukacs, NW, Kennedy, KJ Smith, WS, Hurst, SD and TA Barrett. CC Chemokine-induced differentiation of naive TCR transgenic T cells. J.Immunol. 158:4129-4136, 1997.