Autoreactive T cells from a type I diabetic recognize multiple class II products

Mononuclear cells obtained from a child at the acute presentation of type I diabetes were stimulated in vitro with human insulin followed by IL-2 and IL-4. All of the T-cell clones isolated from this stimulation were autoreactive, recognizing autologous B cells in the absence of insulin or other exogenous antigens. Eleven CD4 + clones were studied in detail to identify the class II MHC antigens stimulating these autoreactive cells. The donor was heterozygous for DR3DQw2 and DR4DQw3.2 haplotypes, a combination of alleles with a greatly increased risk for type I diabetes. The clones demonstrated skewed recognition of class II antigens. Three clones appeared to recognize a peptide derived from one class II β chain (DRβ1, DR4Dw4) presented by another class II β chain (DRβ4, DRw53). Three clones were stimulated by cells expressing DPw4 molecules. Only one clone recognized a product derived from the DR3 haplotype. In contrast to both antigen-specific and autoreactive T-cell clones derived from normal individuals, many of the autoreactive T cells isolated from this subject were stimulated by class II molecules other than DRβ1. The results support the hypothesis that autoreactive T cells recognize autologous peptides in association with MHC and some of these peptides are derived from self MHC molecules.