Indeed, in that study the virus, inoculated through the intraperitoneal route, was cleared rapidly from the thymus but led to a significant increase in CD4-CD8- thymic T cells preceeding the onset of hyperglycaemia. CV-B4 infection of the thymus has been described in human tissue in vitro, and in mice in vivo and in vitro, and the infection results in the disturbance of T cell differentiation/maturation processes [71–76]. The role of alterations

in T lymphocyte subsets in the development of T1D cannot be excluded in so far as they have been observed Buparlisib already in NOD mice [77], in BB rats [78] and also in diabetic patients [79,80]. Whether enterovirus-induced disturbances of thymic cells can play a role in T1D pathogenesis by impairing T cell differentiation and/or central self-tolerance establishment should be investigated further in experimental models in vitro and/or in vivo. For a clearer understanding of the complex interplay between enterovirus and the thymus in the viral pathogenesis of T1D, the link remains to be made between thymus infection and the development of find more the disease in human

beings. Interestingly, in a recent study macrophages infected with an enterovirus (poliovirus) were evidenced in thymus of some patients with myasthenia gravis, suggesting a viral contribution to the intrathymic alterations leading to the disease [81]. Furthermore, CV-A and CV-B have already been found in human perinatal and neonatal thymus in favour of vertical transmission of the viral infection [82,83]. Whether enteroviruses are present in the thymus of patients with T1D or patients in the preclinical stages of the disease merits further study. In T1D, the tolerance of immune system

towards β cells is disturbed at the peripheral level through Treg dysfunction [57]. A disturbance of tolerance at the central level through the infection of thymus with enteroviruses cannot be discarded, and could play a role in the pathogenesis of T1D (see Fig. 2). The potential role of thymus dysfunction in the pathogenesis of T1D opens the possibility of targeting this organ for preventive and therapeutic strategies. Indeed, there are increasing promising insights towards intrathymic manipulation. On the basis of the Metalloexopeptidase close homology and cross-tolerance between insulin, the primary T1D autoantigen and Igf2, the dominant thymic self-antigen of the insulin family, a novel type of vaccination, so-called ‘negative/tolerogenic selfvaccination’, is currently being developed for the prevention and cure of T1D [84]. Conversely, intrathymic manipulation also offers a potential way of enhancing the ability of T cells to control infection by increasing the numbers of positively selected thymocytes able to recognize a given molecule of the corresponding infectious agent.