CTLA-4 is not required for induction of CD8(+) T cell anergy in vivo

Recent studies of T cell anergy induction have produced conflicting conclus ions as to the role of the negative regulatory receptor, CTLA-4. Several in vivo models of tolerance have implicated the interaction of CTLA-4 and its ligands, B7.1 and B7.2, as an essential step in induction of anergy, while results from a number of other systems have indicated that signals from th e TCR/CD3 complex alone are sufficient to induce T cell unresponsiveness. O ne explanation for this disparity is that the requirements for anergy induc tion depend closely on the details of the system: in vivo vs in vitro, rout e of stimulus administration, naive vs memory cells, CD4(+) vs CD8(+) cells , etc. To test this possibility, we established an in vivo anergy model usi ng mice transgenic for the 2C TCR on a recombination-activating gene-2-defi cient background, that either express or lack the CTLA-4 molecule. This sys tem provides us with a very homogeneous pool of naive Ag-specific CD8(+) T cells, allowing us to control some of the conditions mentioned above. We fo und that T cells from CTLA-4-deficient mice were anergized by injections of soluble antigenic peptide as efficiently as were CTLA-4-expressing cells. These results indicate that CTLA-4 is not universally required for in vivo T cell anergy induction and may point to distinctions between regulation of peripheral tolerance in CD4(+) and CD8(+) T cells.