Follicular Regulatory T Cells Are Associated With β-Cell Autoimmunity and the Development of Type 1 Diabetes.

OBJECTIVE: Impaired follicular regulatory T (Tfr) cells enhance T follicular helper cells activity, resulting in the expansion of autoreactive B cells and autoantibody production. However, the role of Tfr cells in the pathogenesis of type 1 diabetes (T1D) is unclear. DESIGN: We evaluated the expression and changes in function of circulating Tfr cells by studying patients with T1D alongside those with type 2 diabetes (T2D), first-degree relatives of T1D patients, and healthy controls. We also investigated the effects of Tfr cells on disease development in nonobese diabetic (NOD) mice and in an adoptive transfer model. RESULTS: Tfr cells were significantly decreased in both patient groups. However, they showed different correlations with fasting C-peptide (C-P) and the area under the curve of blood C-P in patients with T1D and T2D. The frequency of Tfr cells was associated with the number of positive autoantibodies and the titer of glutamic acid decarboxylase autoantibody in T1D patients. Furthermore, Tfr cells decreased significantly after 1 year of follow-up. We also observed Tfr cells in four T1D patients treated with rituximab. After rituximab therapy, the frequency of C-X-C motif chemokine receptor 5 (CXCR5)+ programmed death 1+ Tfr cells was decreased and of CXCR5+ inducible costimulator+ Tfr cells was increased in three patients. We also found that Tfr cells were associated with the development of diabetes in NOD mice and an adoptive transfer model. CONCLUSIONS: Tfr cell deficiency could be involved in the pathogenesis of T1D. Therapy with Tfr cells has potential value for T1D. Modulation of these cells may enhance protective immunity to inhibit autoimmune diabetes.