Diabetes and other autoimmune endocrine diseases
Follicular regulatory T cells (TFR) share many features with follicular helper T cells (TFH) and conventional TREG, i.e. expression of FOXP3, CXCR5 and PD-1. TFR have the role to restrain the B cell helper activity of TFH in germinal centers (GC) preventing autoantibodies (AAbs) production. Islet-specific AAbs are a hallmark of T1D and because islet-specific AAbs are high-affinity and class-switched, they possibly derive from GCs. This implicates TFH and TFR in their development. We investigated the frequency and activation phenotype of circulating TFR from adult subjects with clinical and preclinical T1D (TrialNet). While the frequencies of highly activated TFH (PD-1++) and TFR were higher in pre-symptomatic subjects with high risk for developing T1D as compared to HCs, patients with T1D had a reduced frequency of TFR. Consequently, the TFH/TFR ratio was reduced in pre-symptomatic subjects but increased in T1D patients. Analyses of TFH and TFR in the spleen and pancreatic lymph nodes (PLN) of T1D patients (nPOD and San Raffaele Hospital), identified a reduction in the frequency of TFR as compared to non-diabetic controls. Moreover, spleen-resident TFR from T1D could not suppress B-cell helper responses in vitro. In summary, our findings indicate that while the TFH/TFR equilibrium shifts toward TFR in the blood of pre-symptomatic subjects, it tilts towards TFH in symptomatic individuals. They also suggest that TFR are reduced from a quantitative and qualitative view in the spleen and PLN of T1D patients, suggesting that adoptive transfer of TFR might provide a novel strategy to prevent T1D progression.