Antigen processing and the human T cell receptor repertoire for insulin

Three human T cell lines specific for the A loop of beef insulin were studied to determine the requirements for Ag processing. The data show that the conformation of the A loop of insulin is required for recognition and that the B chain of insulin per se is not necessary for this response. Processing of native insulin was required for responses of all three T cell lines; however, each displayed a different pattern of sensitivity to inhibition of processing and aldehyde fixation of APC. A peptide comprised of two disulfide-linked A chains was partially stimulatory when presented by fixed APC whereas A chain monomers and disulfide-linked A and B chain peptides were not. The response to native insulin, peptides, and A chain dimers was sensitive to chloroquine suggesting that none of these moieties is the terminal processed peptide recognized by insulin immune T cells. The unique patterns of fine specificity, processing requirements, and recognition of aldehyde-fixed antigen-MHC for each T cell line suggest the hypothesis that Ag processing leads to heterogeneity of the T cell repertoire for a single epitope of insulin.