Type 1 Diabetes is a chronic autoimmune disease characterized by the selective loss of insulin producing pancreatic β cells. Its etiology is unclear yet but is thought to have a multifactorial origin involving genetic, environmental and stochastic factors. When tolerance to autoantigens is lost, there is an infiltration of the pancreatic islets with CD8+ T cells, macrophages, CD4+ T cells and B cells, among other cell types that orchestrate their destruction. In T1D tolerance breakdown has been associated to the existence of functional defects and low frequencies of Foxp3+ Treg and iNKT cells in NOD mice. Therefore this study analyzes the regulatory function of human iNKT cells isolated from PBMCS of healthy controls and T1D patients at disease onset. The data show that iNKT cells have the capacity to suppress the proliferation of T effector cells. Interestingly suppression is dependent on the secretion of the cytokine IL-13, a phenomenon that was confirmed when using a blocking antibody to IL-13 resulted on the recovery of T effector cell proliferation. Conversely, regulation was impaired in iNKT cells derived from T1D patients and this functional defect could be related to a decrease in the secretion of IL-13. Since iNKT cells can modulate the function of other immune cells, we analyzed their capacity to interact with Treg cells and improve their regulatory function to better prevent the destruction of pancreatic β cells. The results showed that healthy individuals’ iNKT cells had an adjuvant effect on the suppression of T effector cells by Treg cells. The contribution of iNKT cells was again dependent on the secretion of the immunoregulatory cytokine IL-13 and independent of cell-cell contacts. To understand the possible role of these regulatory cells in T1D, their frequency, anatomical localization and functionality was studied in the pancreas of patients with T1D. We quantified the number of iNKT and Treg cells at different stages of the disease development both in human and NOD mice samples and we analyzed their distribution in and around the pancreatic islets and the exocrine tissue compartment. iNKT and Treg cells showed a differential distribution at disease onset as Tregs were concentrated inside the pancreatic islets while iNKT cells were mainly located in the exocrine tissue. Further, both populations almost disappeared from the pancreas of long-termT1D patients. These results contrasted with those obtained from NOD mice where the frequency of these two populations continued to rise at the diabetic stage. In addition, iNKT and Treg cells isolated from the pancreas of a T1D patient at disease onset were both functional, that is to say that iNKT cells were specific for the glycosphigolipid αGalCer and the Treg cells suppressed the proliferation of T effector cells. Therefore, the set of data shows that alterations in the secretion of IL-13 by iNKT cells at disease onset could lead to the progression of the autoimmune response in T1D. Their cooperation with Treg cells and the presence of both cell types at the target organ of the autoimmune response suggests that their cooperation can take place in situ controlling the destruction of the pancreatic β cells by autoreactive T cells. Thus, the new data on the regulatory function of iNKT cells, the identification of glycosphingolipid agonists enhancing iNKT cells’ IL-13 secretion and the cooperation of Treg and iNKT cells to regulate autoreactive T cells provide a starting point to the design new therapeutic strategies that bypass the constrains of the MHC-restricted immunotherapies.
Date of Award | 1 Feb 2016 |
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Original language | Catalan |
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Awarding Institution | - Universitat Autònoma de Barcelona (UAB)
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Supervisor | Carme Roura Mir (Director) |
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- Type 1 diabetes
- Invariant iNKT
- Regulatory T cells
Estudi de la funció supressora de la cèl·lules iNKT en el control de la resposta autoimmunitària a la Diabetis Tipus 1 humana
Usero Redrejo, L. (Author). 1 Feb 2016
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis