Fig. 10: Model of physiological and diabetogenic autoreactivity against GAD.

In HD (left), GAD-specific clonotypes are selected in the thymus, generating GAD-specific TN cells which seem to include “protective” clonotypes. During neonatal remodelling of the pancreas, physiological beta-cell death occurs, releasing GAD. GAD-specific TN cells get activated by antigen in this context of cell death, initiating a repair mechanism, leading to a fully functional pancreas. During this process, GAD-specific effector and memory cells are generated, presenting phenotype features predisposed to tissue remodelling and repair. Equally, peripherally induced GAD-specific Treg (iTreg) cells are generated and, in potential combination with thymic derived Treg (tTreg) cells and other peripheral tolerance mechanisms, keep the memory GAD cells under control. In T1D patients (right), GAD-specific clonotypes are also selected in the thymus- however, alterations during recombination events generate a repertoire of GAD-specific TN cells that is more public. Additionally, “protective” clonotypes are rarer. During pancreas remodelling and GAD release, an altered physiological autoreactive process occurs: the GAD-specific effector and memory cells generated during the process are of altered phenotypes which are not sufficient to drive appropriate remodelling and repair mechanisms. Additionally, effector and memory cell generation is further fuelled by pre-primed TN cells. As such, beta-cell death continues. Less induced Treg cells are generated and, if so, their phenotypic features do not allow them to contain the effector responses. Thymic Tregs and other peripheral tolerance mechanisms, previously shown to be altered in T1D, cannot contain this diabetogenic autoreactivity. This combination of altered physiological and diabetogenic autoreactivity converge to propel beta cell death, leading to overt T1D. GAD-sp: GAD-specific. Some icons have been created in BioRender. Gomez-tourino, I. (2024) BioRender.com/q46s625.