Programing of the autoimmune diabetogenic response in the thymus during fetal and perinatal life

The presentation of self-peptides in the thymus is responsible both for negative selection of self-reactive T cells emerging during stochastic TCR recombination in fetal life, as well as positive selection of self-specific regulatory thymic T (tTreg) cells during and after perinatal life. The combination of these two sequential processes programs central self-tolerance, a fundamental property of the adaptive immune system. A defect in intrathymic self-presentation, either genetic or acquired, is the earliest event in the pathogenesis of autoimmunity already during fetal development. This defect is necessary but not sufficient for the appearance of a classical autoimmune disease like type 1 diabetes (T1D). Environmental factors are required for activation of the diabetogenic autoimmune response that targets insulin-secreting β cells in pancreatic Langerhans’ islets. Based on epidemiological studies, viral infections have been suspected for a long time to be one of those environmental factors. In this Debate article, we present a series of experimental data that support the hypothesis that, following vertical transplacental transfer, viruses might infect the fetal thymus and disturb already in utero central self-tolerance orchestrated by this organ.