Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I–restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8⁺ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4⁺ T cell help on this process. Small numbers of autoreactive OVA-specific CD8⁺ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic β cells. Coinjection of OVA-specific CD4⁺ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8⁺ T cells indicated that CD4⁺ T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8⁺ T cell tolerance induced by cross-presentation.