Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes
Andrea Vecchione, Tatiana Jofra, Jolanda Gerosa, Kimberly Shankwitz, R. Fonte, Giuseppe Galvani, Elio Ippolito, Maria Pia Cicalese, Andrew Schultz, Howie R. Seay, Μariagrazia Favellato, Giulia Milardi, Angela Stabilini, Francesca Ragogna, Pauline Grogan, Eleonora Bianconi, Andrea Laurenzi, Amelia Caretto, Rita Nano, Raffaela Melzi, Nichole Danzl, Emanuele Bosi, Lorenzo Piemonti, Alessandro Aiuti, Todd M. Brusko, Constantinos Petrovas, Manuela Battaglia, Georgia Fousteri
Abstract
In the attempt to understand the origin of autoantibody (AAb) production in patients with and at risk for type 1 diabetes (T1D), multiple studies have analyzed and reported alterations in T follicular helper (Tfh) cells in presymptomatic AAb+ subjects and patients with T1D. Yet, whether the regulatory counterpart of Tfh cells, represented by T follicular regulatory (Tfr) cells, is similarly altered is still unclear. To address this question, we performed analyses in peripheral blood, spleen, and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb− and AAb+ subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed among T1D, AAb−, and AAb+ adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared with nondiabetic control subjects. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D, suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.