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Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

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posted on 07.10.2021, 16:31 by Andrea Vecchione, Tatiana Jofra, Jolanda Gerosa, Kimberly Shankwitz, Roberta Di Fonte, Giuseppe Galvani, Elio Ippolito, Maria Pia Cicalese, Andrew R. Schultz, Howie R. Seay, Mariagrazia 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 Brusko, Constantinos Petrovas, Manuela Battaglia, Georgia Fousteri
In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. 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-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. 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.

Funding

Italian Ministry of Health JDRF 5-SRA-2018-557-Q-R Leona M. & Harry B. Helmsley Charitable Trust 2018PG-T1D053 Network for Pancreatic Organ NIH P01 AI42288 U01 DK061010 U01 DK061034 U01 DK061042 U01 DK061058 U01 DK085453 U01 DK085461 U01 DK085463 U01 DK085465 U01 DK085466 U01 DK085499 U01 DK085504 U01 DK085505 U01 DK085509 U01 DK103180 U01-DK085476 U01-DK103153 U01-DK103266 nPOD RRID SCR_014641 TMB

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