T cell receptor recognizing proinsulin 76–90 presented by HLA-DRB1*04 (PI76-90/DR4 TCR)

The T cell receptor (TCR) recognizing the proinsulin 76–90 (PI76-90) peptide presented by HLA-DRB1*04:01 is a primary mediator of the autoimmune response in Type 1 Diabetes (T1D). This TCR-pMHC interaction is immunodominant in patients carrying the high-risk HLA-DR4 haplotype, where autoreactive CD4+ T cells escape thymic negative selection and target insulin-producing beta cells in the pancreas. These T cells are characterized by their ability to recognize proinsulin fragments, such as the C-peptide/A-chain junction, and their frequency in peripheral blood correlates with disease progression. Therapeutic strategies targeting this TCR aim to restore immune tolerance through antigen-specific immunotherapy, including the use of soluble peptide vaccines, altered peptide ligands like the 88S variant, and pMHC-coated nanoparticles (Navacims) that induce regulatory T cell (Treg) differentiation. Monitoring the presence and activation state of PI76-90-specific T cells using HLA tetramers and gene expression markers like NR4A serves as a critical biomarker for patient stratification and evaluating the efficacy of tolerogenic treatments.

Other names

Proinsulin 76-90-specific T cell receptorPI76-90/HLA-DR4 TCRProinsulin 73-90-specific T cell receptorPI76-90/HLA-DRB1*04:01 TCRProinsulin-reactive TCR

Antigen-specific immune tolerance induction, regulatory T cell (Treg) expansion, and modulation of TCR-pMHC interaction to prevent beta-cell destruction.