Type 1 diabetes (T1D) is classified into three subtypes: acute onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined.To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D.Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND).We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex-vivo assay involving a 48-h stimulation of peripheral blood mononuclear cells with antigen peptides, and an expansion assay involving intracytoplasmic cytokine analysis.The results of ex-vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses, and preproinsulin (PPI)-specific IP-10 responses, were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte-colony stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed towards type 1 helper T (Th1) cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with HLA-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all four antigens than ND.The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction.