Recognition of human insulin in the context of HLA-DRB1*0406 products by T cells of insulin autoimmune syndrome patients and healthy donors.

Our recent study indicated that all the insulin autoimmune syndrome (IAS) patients had specific HLA class II alleles, the DRB10406, DQA10301, and DQB10302, which allowed T cells to proliferate when autologous APC were exposed to human insulin. The study implied that gene products of DRB10406, DQA10301, and/or DQB10302 may be involved in the presentation of human insulin to T cells. We therefore examined T cell response of healthy donors with different HLA phenotypes to human insulin using an autologous MLR system. The T cells from not only IAS patients but also healthy donors were able to proliferate after exposure of human insulin to autologous APC with DRB10406, DQA10301, and DQB10302 products. The class II molecules are considered to be involved in the recognition of human insulin by T cells. The proliferative response of T cells was completely blocked by anti-HLA-DR mAb and not by anti-HLA-DQ mAb or other mAb. Furthermore, human insulin-specific CD4-positive T cell clones were established from blast cells in autologous MLR of PBMC from two healthy donors with DRB10406 in the presence of human insulin. Using DRB10406-transfected L cells as APC, we confirmed that these T cells clones recognize human insulin in the context of gene products of DRB10406. These results provide the first evidence that HLA-DRB10406 products act as the dominant restriction element for the presentation of human insulin to T cells, and suggest that this particular class II gene, HLA-DRB10406, contributes to the development of IAS.