Previous cross-sectional analyses demonstrated that CD8⁺ and CD4⁺ T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4⁺ T-cell cytokine production and autoreactive CD8⁺ T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4⁺ T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD. In contrast, higher frequencies of islet antigen-specific CD8⁺ T-cells were detected only in T1D. These observations support the hypothesis that general beta-cell stress drives autoreactive CD4⁺ T-cell activity while islet over-expression of MHC class I commonly seen in T1D mediates amplification of CD8⁺ T-cells and more rapid beta-cell loss. In conclusion, CD4⁺ T-cell autoreactivity appears to be present in both T1D and T2D while autoreactive CD8⁺ T-cells are unique to T1D. Thus, autoreactive CD8⁺ cells may serve as a more T1D-specific biomarker.