An intra-Peyer's patch gene transfer model for studying mucosal tolerance: distinct roles of B7 and IL-12 in mucosal T cell tolerance.
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-gamma 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-gamma production. By contrast, intra-Peyer's patch IL-12 gene transfer completely restored T cell proliferation and IFN-gamma 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-gamma production, whereas IL-12 increased both IL-2 and IFN-gamma 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.
Chen
Y
Y
Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. yhc@mail.med.upenn.edu
Song
K
K
Eck
S L
SL
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007272:Injections, Intralymphatic; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018448:Models, Immunological; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010581:Peyer's Patches / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
D018122:B7-1 Antigen; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin