Aims/hypothesis. Preproinsulin is a target T cell autoantigen in human Type 1 diabetes. This study analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (auto-antibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabetic patients. Methods. A preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4 + CD45RA − and CD4 + CD45RA + T cell subfractions, representing memory and naive and recently primed T cells respectively. Results. In CD4 + T cell subsets we identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabetic HLA-matched control subjects. In Ab+ subjects, a C-peptide epitope C13-29 and insulin B-chain epitope B11-27 were preferentially recognised, whereas insulin-treated Type 1 diabetic patients reacted to native insulin and B-chain epitope B1-16. In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNγ, IL-2) and Th2 (IL-4) cytokines was detectable, wheras in CD45RA + and CD45RA − subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNγ content. In insulintreated Type 1 diabetic patients, naive and recently primed CD4 + cells were characterised by increasd IFNγ, TNFα, and IL-5. Conclusions/interpretation. Our data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2-dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes. Characteristic immunodominant epitopes and cytokine patterns distinguish diabetic patients and Ab+ subjects from HLAmatched healthy individuals. This could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials. [Diabetologia (2004) 47:439-450]

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