Fatoumata Samassa1, Capucine Holtzmann1,2 and Roberto Mallone1,3,4 1Université Paris Cité, Institut Cochin, CNRS, INSERM, Cochin-Port-Royal, Bâtiment Cassini - 123, F-75014 Paris, France 2Ecole Normale Supérieure, F-69342 Lyon, France 3Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, F-75014 Paris, France 4Indiana Biosciences Research Institute, Indianapolis, Indiana 46202, USA Correspondence: roberto.malloneinserm.fr

Type 1 diabetes (T1D) is a disease whose pathogenesis is driven by both immune dysregulation and β-cell dysfunction. While the specialized structure and function of β cells make them vulnerable to autoimmunity, several surface receptor/ligand pairs underlie the cross talk engaged with T lymphocytes and other immune subsets. The expression of these ligands on β cells is coordinately up-regulated by the exposure to interferons, notably the type I interferons that represent the signature cytokines since the early preclinical stages of T1D. Yet, their interaction with receptors expressed on T lymphocytes can favor either β-cell vulnerability or protection. Despite several knowledge gaps, this novel holistic view of autoimmunity that incorporates both immune and β-cell-derived pathogenic drivers is starting to translate into novel therapeutic strategies aimed at decreasing vulnerability and/or increasing these protective mechanisms. This review summarizes the current knowledge in this evolving field, the assumptions that are often taken for granted but lack formal evidence, and the blind spots in this landscape that may hide further therapeutic opportunities.