Glutamate decarboxylase 65-specific T-cell receptor (GAD65-specific TCR)

Glutamate decarboxylase 65-specific T-cell receptors (GAD65-specific TCRs) are antigen-recognition proteins expressed on the surface of CD4+ T lymphocytes that specifically bind to peptides derived from the GAD65 autoantigen when presented by Major Histocompatibility Complex (MHC) class II molecules, such as HLA-DR4 or HLA-DQ8 (Kwok et al., 2002, JCI). GAD65 is a primary target of the autoimmune attack in Type 1 Diabetes (T1D), and the activation of these TCRs by GAD65-MHC II complexes triggers the release of pro-inflammatory cytokines and the subsequent destruction of insulin-producing pancreatic beta cells (Pihoker et al., 2005, Diabetes Care). These TCRs are also implicated in the pathogenesis of Stiff-person syndrome, where high titers of GAD65 autoantibodies and reactive T cells are observed. Therapeutic strategies targeting these TCRs aim to preserve beta-cell function by inducing immune tolerance through GAD65-specific vaccines, such as Diamyd, or by using engineered regulatory T cells (Tregs) to suppress the autoreactive response (Ludvigsson et al., 2012, NEJM; Hull et al., 2020, Front Immunol). Additionally, monoclonal antibodies like Teplizumab modulate the activity of these T cells by targeting the CD3 complex associated with the TCR, thereby delaying the progression of T1D in high-risk individuals.

Other names

GAD65-reactive T-cell receptorGAD-specific TCRGAD65-specific CD4+ T-cell receptorGlutamate decarboxylase 2-specific T-cell receptorGAD65-MHC II-specific TCR

Modulation of autoreactive T-cell activity through induction of immune tolerance, competitive inhibition of antigen recognition, or selective depletion of GAD65-reactive T-cell clones.