Type 1 diabetes results from the destruction of pancreatic beta cells by a specifi c autoimmune process. beta cell autoantigens, macrophages, dendritic, B and T cells have been shown to be involved in the pathogenesis of diabetes mellitus 1. The autoantigens are released from beta-cells by cellular turnover or damage and are processed and presented to T helper cells by antigen-presenting cells. Macrophages and dendritic cells (DCs) are the first cell types to infiltrate the pancreatic islets. Naive CD4+ T cells that circulate in the blood and lymphoid organs, including the pancreatic lymph nodes, may recognize major histocompatibility complex and beta-cell peptides presented by dendritic cells and macrophages in the islets. These CD4+ T cells can be activated by interleukin (IL)-12 released from macrophages and DCs. While this process takes place, beta cell antigen-specifi c CD8+ T cells are activated by IL-2 produced by the activated TH1 CD4+ Tcells, differentiate into cytotoxic Tcells and are recruited into the pancreatic islets. These activated TH1 CD4+ Tcells and CD8+ cytotoxic Tcells are involved in the destruction of beta cells. In addition, beta cells can also be damaged by granzymes and perforin released from CD8+ cytotoxic T cells and by soluble mediators such as cytokines and reactive oxygen molecules released from activated macrophages in the islets. Thus, activated macrophages, TH1 CD4+ T cells, and cell-cytotoxic CD8+ T cells act synergistically to destroy beta cells, resulting in type 1 diabetes.