Pre-proinsulin peptide-HLA-A2 complex (PPI-HLA-A2)

The Pre-proinsulin peptide-HLA-A2 complex is a specific peptide-major histocompatibility complex (pMHC) class I molecule that plays a central role in the autoimmune destruction of pancreatic beta cells in Type 1 Diabetes (T1D). Pre-proinsulin (PPI) is the foremost autoantigen in T1D, and its signal peptide—specifically the PPI 15-24 epitope (ALWGPDPAAA)—is presented by the HLA-A*02:01 molecule (Skowera et al., 2008, J Clin Invest). This complex is recognized by pathogenic CD8+ T cells, which are found in the pancreatic infiltrates of T1D patients and are responsible for killing insulin-producing cells (Knight et al., 2013, Diabetes). Because the HLA-A2 allele is highly prevalent and associated with early-onset T1D, this pMHC complex is a major target for precision immunotherapies (Lutter et al., 2020, Diabetologia). Current drug development efforts, such as soluble TCR-bispecifics like IMC-I109V, aim to redirect or suppress the immune response specifically against this complex to prevent disease progression (Immunocore, 2023). Additionally, the complex is used in tetramer assays to monitor the frequency of autoreactive T cells as a biomarker for disease activity and therapeutic response (Velthuis et al., 2010, Diabetes).

Other names

Preproinsulin/HLA-A*02:01 complexPPI15-24-HLA-A2Insulin signal peptide-HLA-A2 complexpMHC complex (PPI/HLA-A2)

Targeting of autoreactive T cells or induction of immune tolerance through specific recognition of the pre-proinsulin epitope presented by HLA-A2.