NKT cell activation by α-galactosylceramide (α-GalCer) inhibits autoimmune diabetes in NOD mice, in part by inducing recruitment to pancreatic lymph nodes (PLNs) of mature dendritic cells (DCs) with disease-protective effects. However, how activated NKT cells promote DC maturation, and what downstream effect this has on diabetogenic T cells was unknown. Activated NKT cells were found to produce a soluble factor(s) inducing DC maturation. Initially, there was a preferential accumulation of mature DCs in the PLNs of α-GalCer-treated NOD mice, followed by a substantial increase in T cells. Adoptive transfer of a diabetogenic CD8 T cell population (AI4) induced a high rate of disease (75%) in PBS-treated NOD recipients, but not in those pretreated with α-GalCer (8%). Significantly, more AI4 T cells accumulated in PLNs of α-GalCer than PBS-treated recipients, while no differences were found in mesenteric lymph nodes from each group. Compared with those in mesenteric lymph nodes, AI4 T cells entering PLNs underwent greater levels of apoptosis, and the survivors became functionally anergic. NKT cell activation enhanced this process. Hence, activated NKT cells elicit diabetes protection in NOD mice by producing a soluble factor(s) that induces DC maturation and accumulation in PLNs, where they subsequently recruit and tolerize pathogenic T cells.

Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet ␤ cells. Cytotoxic CD8 ؉ T cells, reactive to ␤ cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8 ؉ T cells specific for ␤ cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8 ؉ T cell clone AI4, to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with ␤ cell antigens leads to deletion of autoreactive CD8 ؉ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.autoimmune disease ͉ type 1 diabetes T ype 1 diabetes (T1D) is an autoimmune disease characterized by an inability to establish and maintain tolerance to ␤ cell antigens. In diabetes-prone individuals, autoreactive T cells respond to pancreatic islet ␤ cell antigens in conjunction with costimulatory signals, promoting initial T cell activation resulting in selective expansion, differentiation, islet invasion, and ultimately destruction of ␤ cells (1). Clinically, the end result is the inability of the affected individual to produce the insulin required to properly regulate glucose metabolism. NOD mice provide a model system for T1D that shares many of the characteristics of the human disease (2). Multiple lines of investigation have demonstrated the importance of CD8 ϩ T cells in the pathogenesis of T1D in NOD mice (3). This is consistent with the detection of islet antigen-specific CD8 ϩ T cells in the peripheral blood of T1D patients (4). Using CD8 ϩ T cells derived from the islets of NOD mice, a limited number of ␤ cell antigens recognized by islet-infiltrating T cells have been identified (4). Lack of availability of a therapy for T1D other than insulin administration inspires the usage of ␤ cell antigens and epitopes targeted by T cells in T1D to develop antigen-based tolerogenic strategies.As reviewed (5), dendritic cells (DCs) in the steady state, e.g., in the absence of infection, present antigens in a tolerogenic manner and cause naive CD8 ϩ T cells to proliferate initially but then to be deleted or rendered unresponsive. The pathway by wh...

T cell-mediated autoimmune type-1 diabetes (T1D) in NOD mice partly results from this strain’s numerical and functional defects in invariant NK T (iNKT) cells. T1D is inhibited in NOD mice treated with the iNKT cell superagonist α-galactosylceramide through a process involving enhanced accumulation of immunotolerogenic dendritic cells in pancreatic lymph nodes. Conversely, T1D is accelerated in NOD mice lacking CD38 molecules that play a role in dendritic cell migration to inflamed tissues. Unlike in standard NOD mice, α-galactosylceramide pretreatment did not protect the CD38-deficient stock from T1D induced by an adoptively transferred pancreatic β cell-autoreactive CD8 T cell clone (AI4). We found that in the absence of CD38, ADP-ribosyltransferase 2 preferentially activates apoptotic deletion of peripheral iNKT cells, especially the CD4+ subset. Therefore, this study documents a previously unrecognized role for CD38 in maintaining survival of an iNKT cell subset that preferentially contributes to the maintenance of immunological tolerance.