Physiology of anergic CD8 T cells in a transgenic mouse model

Within the T cell system, self-tolerance is mainly maintained by thymic clonal deletion of self-reactive T cells through the mechanism of negative selection. However some self-reactive T cells escape negative selection and reach the lymphoid periphery where other mechanisms maintain tolerance. To study the peripheral tolerance mechanisms we are using a mouse experimental model of peripheral non-deletional tolerance. In this double transgenic mouse model the antigen, an influenza nucleoprotein peptide is widely expressed under the MHC I H-2Kb promoter and all CD8 T cells carry a transgenic TCR specific for the influenza peptide presented by MHC H-2Db. Thymic selection of these T cells proceeds normally without deletion, but peripheral tolerance is maintained. The NP-specific T cells are functionally compromised in vitro to antigenic stimulation and are characterised by a CD44high activated phenotype. However these cells, upon transfer to antigen free lymphopenic host can be rescued from the anergic state, undergo several homeostatic divisions and show a long life span. Further more investigation on the functional capacities of the NP47F5 CD8 T cells showed that they could have cytotoxic capacity. Therefore, although they appear to be functionally compromised in vitro, they can react in vivo. These functional characteristics indicate that these cells are not totally anergic, as they can have effector functions. These functional characteristics also indicate that these cells could be auto reactive in vivo, and it could be that the site of Ag expression (Bone Marrow derived cells) that accounts for the lack of measurable tissue damage. The long life span and the functional characteristics may also indicate that they could play a functional role in the maintenance of peripheral tolerance