IL-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-helper-17 Cells at the Expense of Regulatory T cells: Implications for the Timing of Tolerizing Immunotherapy

Abstract

The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DC), is greater when administered to young NOD mice than at peak insulitis. RelBlo DC, generated in the presence of an NF-kB inhibitor, induce T regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. IL-1b is over-expressed in humans and mice at risk of T1DM, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1b production and the response to RelBlo DC in the pre-diabetic period. We injected RelBlo DC s.c. into 4- or 14-week-old NOD mice, and tracked the incidence of diabetes and effect on Treg cell function. We measured IL-1b production by stimulated splenocytes from mice of different ages and strains, and proliferative and cytokine responses of T effectors to Treg in vitro. Tolerising RelBlo DC significantly inhibited diabetes progression when administered to 4-week-old but not 14 week old mice. IL-1b production by NOD splenocytes was increased from 6 to 16 weeks of age, when MHC-restricted islet antigen presentation to autoreactive T cells occurred. IL-1 promoted Th17 cells and reduced the capacity of Treg cells to suppress effector cells. RelBlo DC exacerbated the IL-1-dependent decline in Treg function and promoted Th17. IL-1b, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC-therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1b/IL-17 checkpoint signals the need for other strategies.