Upon encounter with foreign antigen, tissue-associated antigen-presenting cells (APCs) migrate to draining lymph nodes to prime specific T cells. Using the transgenic RIP-mOVA model, we recently demonstrated that self antigens derived from peripheral tissues are constitutively transported to draining lymph nodes, and can be presented in association with MHC class I molecules by a bone marrow-derived APC population. This form of class I-restricted presentation of exogenous antigen has been referred to as cross-presentation and can induce activation and proliferation of antigen-specific CD8+ T cells. In the absence of CD4+ T cell help, activation of CD8+ T cells is inefficient, and cross-presentation leads to peripheral deletion of autoreactive CD8+ T cells, acting as a mechanism to maintain self-tolerance. If CD4+ T cell help is available, CD8+ T cell responses to self antigens can be rendered immunogenic, leading to autoreactive responses. Whether autoimmunity results from such responses also depends on the tissue location of the antigen. In RIP-mOVA mice, which express the model antigen mOVA (a membrane-bound form of ovalbumin) in the pancreatic beta cells and kidney proximal tubules, OVA-specific CD8+ T cells, activated by cross-presentation, infiltrated the pancreas and caused B cell destruction. Interestingly, however, these cells did not infiltrate the kidney, suggesting that proximal tubular cells are to some extent protected from immune destruction. Analysis of the role of antigen concentration indicates that high doses were required for efficient cross-presentation, suggesting that this pathway is directed towards immune responses to high-dose antigens, such as may be present during viral infection.