Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T‐lymphocyte antigen‐4

Summary CD4+ Foxp3+ regulatory T (Treg) cells can control both cellular and humoral immune responses; however, when and how Treg cells play a predominant role in regulating autoimmune disease remains elusive. To deplete Treg cells in vivo at given time‐points, we used a mouse strain, susceptible to glucose‐6‐phosphate isomerase peptide‐induced arthritis (GIA), in which the deletion of Treg cells can be controlled by diphtheria toxin treatment. By depleting Treg cells in the GIA mouse model, we found that a temporary lack of Treg cells at both priming and onset exaggerated disease development. Ablation of Treg cells led to the expansion of antigen‐specific CD4+ T cells including granulocyte–macrophage colony‐stimulating factor, interferon‐γ and interleukin‐17‐producing T cells, and promoted both T‐cell and B‐cell epitope spreading, which perpetuated arthritis. Interestingly, specific depletion of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) on Treg cells only, was sufficient to protect mice from GIA, due to the expansion of CTLA‐4− Treg cells expressing alternative suppressive molecules. Collectively, our findings suggest that Treg cells, independently of CTLA‐4, act as the key driving force in controlling autoimmune arthritis development. Transient imbalance between regulatory T (Treg) cells and effector T cells during activation of autoreactive T cells results in a long‐impact on autoimmune arthritis. The loss of Treg cells is a trigger for a chain reaction of activating autoreactive T cells, expanding plasma cells and, most importantly, inducing T‐cell and B‐cell epitope spreading to joint‐specific epitopes.