This study investigates the induction of peripheral T cell tolerance in vivo and shows that it requires engagement of CTLA-4 with B7 molecules. In contrast, blocking CD28 does not prevent tolerance induction. The results suggest that T cell anergy in vivo is not due to a lack of costimulation, but rather to specific recognition of B7 molecules by CTLA-4. T cells exposed to tolerogenic antigen in vivo showed reduced proliferation and cytokine production, indicating functional unresponsiveness. However, blocking B7 molecules prevented these changes, maintaining T cells in an unactivated but functionally competent state. Similarly, blocking CTLA-4 prevented the induction of tolerance, indicating that CTLA-4 engagement is necessary for tolerance induction. These findings suggest that the outcome of antigen recognition by T cells depends on the interaction of CD28 or CTLA-4 with B7 molecules. The study also shows that the induction of T cell tolerance requires CTLA-4 engagement with B7 molecules on antigen-presenting cells. This is in contrast to the role of CD28 in T cell priming. The results suggest that the level and duration of costimulation determine the outcome of antigen recognition by T cells. In the absence of costimulation, T cells do not respond to antigen, leading to "ignorance" or programmed cell death. With low levels of costimulation, T cells may engage B7 via CTLA-4 and become anergic. Blocking CTLA-4 may prevent anergy induction or enhance the production of growth factors that prevent or reverse anergy. In contrast, higher levels of B7 expression may lead to sustained CD28 engagement and a normal T cell response. The study highlights the importance of costimulation in T cell activation and tolerance induction, and suggests that optimal strategies for inducing T cell activation or tolerance may require fine controls on the nature, level, and duration of costimulation at the time of antigen recognition, along with regulating the balance between CD28- and CTLA-4-triggered signals.This study investigates the induction of peripheral T cell tolerance in vivo and shows that it requires engagement of CTLA-4 with B7 molecules. In contrast, blocking CD28 does not prevent tolerance induction. The results suggest that T cell anergy in vivo is not due to a lack of costimulation, but rather to specific recognition of B7 molecules by CTLA-4. T cells exposed to tolerogenic antigen in vivo showed reduced proliferation and cytokine production, indicating functional unresponsiveness. However, blocking B7 molecules prevented these changes, maintaining T cells in an unactivated but functionally competent state. Similarly, blocking CTLA-4 prevented the induction of tolerance, indicating that CTLA-4 engagement is necessary for tolerance induction. These findings suggest that the outcome of antigen recognition by T cells depends on the interaction of CD28 or CTLA-4 with B7 molecules. The study also shows that the induction of T cell tolerance requires CTLA-4 engagement with B7 molecules on antigen-presenting cells. This is in contrast to the role of CD28 in T cell priming. The results suggest that the level and duration of costimulation determine the outcome of antigen recognition by T cells. In the absence of costimulation, T cells do not respond to antigen, leading to "ignorance" or programmed cell death. With low levels of costimulation, T cells may engage B7 via CTLA-4 and become anergic. Blocking CTLA-4 may prevent anergy induction or enhance the production of growth factors that prevent or reverse anergy. In contrast, higher levels of B7 expression may lead to sustained CD28 engagement and a normal T cell response. The study highlights the importance of costimulation in T cell activation and tolerance induction, and suggests that optimal strategies for inducing T cell activation or tolerance may require fine controls on the nature, level, and duration of costimulation at the time of antigen recognition, along with regulating the balance between CD28- and CTLA-4-triggered signals.