Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade

Rodent models of arthritis have been extensively used in the elucidation of rheumatoid arthritis (RA) pathogenesis and are instrumental in the development of therapeutic strategies. Here we utilise delayed-type hypersensitivity arthritis (DTHA), a model in C57BL/6 mice affecting one paw with synchronised onset, 100% penetrance and low variation. We investigate the role of regulatory T cells (T(regs)) in DTHA through selective depletion of T(regs) and the role of IL-17 in connection with T(reg) depletion. Given the relevance of T(regs) in RA, and the possibility of developing T(reg)-directed therapies, this approach could be relevant for advancing the understanding of T(regs) in inflammatory arthritis. Selective depletion of T(regs) was achieved using a Foxp3-DTR-eGFP mouse, which expresses the diphtheria toxin receptor (DTR) and enhanced green fluorescent protein (eGFP) under control of the Foxp3 gene. Anti-IL-17 monoclonal antibody (mAb) was used for IL-17 blockade. Numbers and activation of T(regs) increased in the paw and its draining lymph node in DTHA, and depletion of T(regs) resulted in exacerbation of disease as shown by increased paw swelling, increased infiltration of inflammatory cells, increased bone remodelling and increased production of inflammatory mediators, as well as increased production of anti-citrullinated protein antibodies. Anti-IL-17 mAb treatment demonstrated that IL-17 is important for disease severity in both the presence and absence of T(regs), and that IL-17 blockade is able to rescue mice from the exacerbated disease caused by T(reg) depletion and caused a reduction in RANKL, IL-6 and the number of neutrophils. We show that T(regs) are important for the containment of inflammation and bone remodelling in DTHA. To our knowledge, this is the first study using the Foxp3-DTR-eGFP mouse on a C57BL/6 background for T(reg) depletion in an arthritis model, and we here demonstrate the usefulness of the approach to study the role of T(regs) and IL-17 in arthritis.