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An Intra-Peyer’s Patch Gene Transfer Model for Studying Mucosal Tolerance: Distinct Roles of B7 and IL-12 in Mucosal T Cell Tolerance¹

Yiguang Chen^*, Kaimei Song^*, Stephen L. Eck and Youhai Chen^2,*

^* Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Development of mucosal immunity and tolerance requires coordinated expression of a number of genes within the mucosa-associated lymphoid tissue (MALT). To study the roles of these genes in the MALT, we have established a MALT-specific gene transfer model using replication-defective adenovirus as vector. In this model, the target gene of interest is directly delivered into the Peyer’s patch by intra-Peyer’s patch injection of the recombinant virus. Using this gene transfer model, we investigated the roles of B7-1 and IL-12 in the development of mucosal tolerance. We found that intra-Peyer’s patch injection of OVA induced Ag-specific T cell hyporesponsiveness, as manifested by decreased T cell proliferation and IL-2/IFN- production upon subsequent immune challenge. Intra-Peyer’s patch B7-1 gene transfer at the time of OVA administration partially reversed the inhibition of T cell proliferation and IL-2 secretion, but had no effect on IFN- production. By contrast, intra-Peyer’s patch IL-12 gene transfer completely restored T cell proliferation and IFN- secretion and partially reversed IL-2 inhibition. Using an adoptive TCR transgenic model, we further demonstrated that B7 and IL-12 played distinct roles during the inductive phase of mucosal tolerance. B7 selectively increased T cell proliferation and IL-2 secretion without affecting IFN- production, whereas IL-12 increased both IL-2 and IFN- production. These results indicate that B7 alone may not be sufficient to abrogate mucosal tolerance, and that cytokines such as IL-12 may also be required. Based on these findings, we propose a new model to explain the paradoxical roles of B7 in mucosal immunity and tolerance.

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