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While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T cells in the destruction of pancreatic islets is well characterized, but immune-mediated mechanisms that contribute to T1D protection have not been fully elucidated. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules. In this review, we summarize what is known about the antigenic self-peptides recognized by Tregs in the context of T1D.