Development of human autoimmune disorders results from complex interplay among genetic, environmental, and immunological risk factors. Despite much heterogeneity in environmental triggers, the leading genes that give the propensity for tissue-specific autoimmune diseases, such as type 1 diabetes, are those associated with particular class II major histocompatibility complex alleles. Such genetic predisposition precipitates presentation of tissue antigens to MHC-II-restricted CD4 T cells. When properly activated, these self-reactive CD4 T cells migrate to the target tissue and trigger the initial immune attack. Using the non-obese diabetic mouse model of spontaneous autoimmune diabetes, much insight has been gained in understanding how presentation of physiological levels of self-antigens translates into pathological outcomes. In this review, we summarize recent advances illustrating the features of the antigen presenting cells, the sites of the antigen recognition, and the nature of the consequent T cell responses. We emphasize emerging evidence that highlights the importance of systemic presentation of catabolized tissue antigens in mobilization of pathogenic T cells. The implication of these studies in therapeutic perspectives is also discussed.