Distinct Phenotypes of Islet Antigen-specific CD4+ T Cells among the Three Subtypes of Type 1 Diabetes.

CONTEXT: 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.

OBJECTIVE: To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D.

PARTICIPANTS: Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND).

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.