Title

Establishment of an in vivo model system for activation, migration and memory generation of CD8 T cells in the intestinal mucosa

Date of Completion

January 2000

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

A novel experimental system was established in which the fate of antigen-specific CD8 T cells could be followed in vivo with regard to the secondary lymphoid tissues and the intestinal mucosa. Immunization with soluble ovalbumin (tolerizing regimen) induces activation and migration of ovalbumin-specific CD8 T cells (OT-1) into the effector sites of the intestinal mucosa (the lamina propria and the intraepithelial lymphocyte compartment). The OT-1 migrants exhibit functional differentiation (CTL induction) in the intestinal mucosa but not elsewhere, possibly due to the chronic inflammatory nature of the intestine. The immunogenic challenge of mice with VSV expressing ovalbumin (VSV-ova) induces a potent antigen-specific CD8 T cell response accompanying robust CTL activity in the spleen and lymph nodes as well as the intestinal mucosa. The expansion phase is soon followed by the disappearance of activated CD8 T cells, possibly mediated through activation-induced cell death (AICD). Small numbers of OT-1 CD8 T cells survive the death phase and become long-lived memory T cells. Memory T cells are not only detected in the secondary lymphoid tissues but also in the intestinal mucosa. Phenotypic analyses suggest that the intestinal mucosa-specific memory T cells are maintained independently of the memory T cells in the secondary lymphoid tissues. Functionally, memory OT-1 CD8 T cells exhibit low but significant levels of antigen-specific cytotoxicity without in vitro reactivation and are capable of rapidly producing IFN-γ. Memory T cells are reactivated upon soluble ovalbumin feeding, measured by an increase in cell size and cytotoxicity. Unlike the costimulation-dependent primary response, reactivation of memory cells does not require B7-1 and B7-2-mediated costimulatory signals. Thus, we hypothesize that the intestinal mucosa-specific memory T cells are critically involved in the protection against pathogens that enter through the intestinal mucosa. The system established here will provide a powerful tool to investigate the CD8 T cell response in vivo and eventually provide the basis for more efficacious vaccine development or effective regimens to treat the inflammatory diseases of the gut. ^