Tolerance breakdown in Type 1 Diabetes (T1D) has been associated in part to frequency and functional defects of iNKT cells favoring the development of T1D in NOD mice. Thus, to determine if human NKT cells could play a role in the control of T1D development, we have studied if iNKT cells derived from human T1D patients and healthy donors could exert a regulatory function.
We demonstrated that iNKT cells have the capacity to suppress the proliferation of T effector cells (Teff). Interestingly, suppression was dependent on the secretion of the cytokine IL-13 since addition of a blocking antibody to IL-13 resulted on Teff cell proliferation and IL2 secretion recovery. However, this regulatory mechanism was clearly impaired in iNKT cells isolated from blood or pancreas of T1D patients at disease onset. Further, their functional defect could be related both to a decreased secretion of IL-13 by iNKT cells and to a different expression pattern of the IL13 receptor in Teff cells from these patients compared to controls. These results indicated that the alteration of this regulatory pathway in T1D patients can favor progression of the autoimmune response to T1D. In order to elucidate the reason behind this functional defect a gene expression analysis has been performed to identify molecules and/or pathways that could be related to the regulation impairment in T1D patients. Confirmation of these results should provide a new immunotherapeutic approach for T1D using iNKT cells.