Interleukin-13 Pathway Alterations Impair Invariant Natural Killer T-Cell–Mediated Regulation of Effector T Cells in Type 1 Diabetes

Abstract

Many studies have shown that human natural killer T (NKT) cells can promote immunity to pathogens, but their regulatory function is still being investigated. Invariant NKT (iNKT) cells have been shown to be effective in preventing type 1 diabetes in the NOD mouse model. Activation of plasmacytoid dendritic cells, modulation of B-cell responses, and immune deviation were proposed to be responsible for the suppressive effect of iNKT cells. We studied the regulatory capacity of human iNKT cells from control subjects and patients with type 1 diabetes (T1D) at disease clinical onset. We demonstrate that control iNKT cells suppress the proliferation of effector T cells (Teffs) through a cell contact–independent mechanism. Of note, suppression depended on the secretion of interleukin-13 (IL-13) by iNKT cells because an antibody blocking this cytokine resulted from the abrogation of Teff suppression; however, T1D-derived iNKT cells showed impaired regulation that could be attributed to the decrease in IL-13 secretion. Thus, alteration of the IL-13 pathway at disease onset may lead to the progression of the autoimmune response in T1D. Advances in the study of iNKT cells and the selection of agonists potentiating IL-13 secretion should permit new therapeutic strategies to prevent the development of T1D.

Defective Invariant Natural Killer T-Cell Suppression in Patients With Type 1 Diabetes

“…Defective Th2 cytokine production could be due to iNKT cell repolarization and/or the depletion of CD4 + iNKT cell subset preferentially producing anti-inflammatory cytokines, as reported by Kis et al (13). Although Usero et al (8) describe a direct effect of iNKT cells on effector T cells, it remains to be addressed whether iNKT cells from T1D patients could modify dendritic cell (DC) function. It has been well established in mouse models that iNKT cells can induce tolerogenic DCs generating Treg cells in the pancreatic lymph nodes (14)(15)(16).…”

“…The current study (8) and others have described a decrease of IL-13 and IL-4 production by iNKT cells in T1D patients. It would be important to determine whether these abnormalities are restricted to the production of these cytokines or rather reflect a more generally altered status.…”

“…In this issue, Usero et al (8) show for the first time in vitro that iNKT cell suppression of T-cell response is defective in T1D patients. iNKT cells from healthy control subjects ex vivo and after expansion in vitro suppress interleukin (IL)-2 synthesis and the proliferation of effector T cells (CD4 + CD25 2 ) via a mechanism independent of cell contact (Fig.…”

“…Previous studies in T1D patients have reported a decrease of IL-4 production by iNKT cells from the peripheral blood and pancreatic lymph nodes (11,12). It would have been interesting if Usero et al (8) had measured IL-4 production by iNKT cells from recentonset T1D patients. Defective Th2 cytokine production could be due to iNKT cell repolarization and/or the depletion of CD4 + iNKT cell subset preferentially producing anti-inflammatory cytokines, as reported by Kis et al (13).…”

“…1E). Of note, Usero et al (8) do not analyze iNKT frequency in T1D patients and therefore do not shed a new light on this controversial issue (18,19). Moreover, as T1D particularly affects children and is diagnosed more and more early in childhood, it would be interesting to perform a similar study in children with recent-onset diabetes.…”