AUTHOR=Mendes-da-Cruz Daniella A. , Lemos Julia P. , Passos Geraldo A. , Savino Wilson 

TITLE=Abnormal T-Cell Development in the Thymus of Non-obese Diabetic Mice: Possible Relationship With the Pathogenesis of Type 1 Autoimmune Diabetes

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00381

DOI=10.3389/fendo.2018.00381

ISSN=1664-2392

ABSTRACT=Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells in the pancreas, by direct interactions with autoreactive pancreas infiltrating T lymphocytes (PILs). One of the most important animal models for this disease is the non-obese diabetic (NOD) mouse. Alterations in the NOD mouse thymus during the pathogenesis of the disease have been reported. From the initial migratory disturbances to the accumulation of mature thymocytes, including regulatory Foxp3+ T cells, important mechanisms seem to regulate the repertoire of T cells that leave the thymus to settle in peripheral lymphoid organs. An important disturbance in NOD mouse thymocyte migration is associated to a defect in the membrane expression of the fibronectin receptor VLA-5 (alpha5/beta1 integrin). Yet, the modulation of other integrins and chemokine receptors may also contribute to the progressive accumulation of mature thymocytes and consequent formation of giant perivascular spaces (PVS) in the NOD thymus. These intrathymic giant PVS are also filled with a typical ECM network that differs from the pattern seen in the thymus parenchyma. Comparative large-scale transcriptional expression and network analyses involving mRNAs and miRNAs of thymocytes, peripheral T CD3+ cells and PILs provided evidence that in PILs the CCR7 chemokine receptor and CD247 mRNAs are post-transcriptionally regulated by miR-202-3p resulting in decreased activity of these molecules during the onset of T1D in NOD mice. In this review, we will discuss the abnormal T-cell development in NOD mice in the context of intrathymic expression of peptides belonging to the family of insulin and insulin-like growth factors as well as the participation of miRNAs as post-transcriptional regulators and their possible influence on the onset of aggressive autoimmunity during the pathogenesis of T1D.