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

Abstract

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.

Deep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity

“…Prior studies show that immune traits can be associated with specific genetic loci, including autoimmunityassociated single-nucleotide polymorphisms. These traits include immune subsets dysregulated in DS (such as decreased CXCR5 + B cells with Sjögren's syndrome-associated ds4938573 and increased T H 1 cells with PTPN22 C1858T) (73)(74)(75) and immune features associated with increased risk of autoimmunity in TCs (76,77). These findings support the notion that trisomy 21 alters immune architecture in ways that are associated with, and might drive, increased risk of autoimmunity.…”

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

“…Vecchione et al. have reported that the frequency of CXCR5 − FOXP3 + Tregs was higher in AAb + patients than in AAb − patients, which may be caused by active autoimmunity and metabolic dysfunction in AAb + patients 279 3), which were needed to maintain peripheral tolerance by regulating diabetogenic Tfhs and B cells, were reduced in spleen and pancreatic lymph node of patients with T1D.…”

“…Treg subsets in type 1 diabetes T1D, a chronic autoimmune disorder, is characterized by insulin deficiency and resultant hyperglycaemia. [277][278][279] The complex interactions between the pancreatic β-cell and innate and adaptive immune systems lead to the progression of T1D. 280 In humans, Tfrs are identified that can inhibit the production of AAbs and restore glucose tolerance.…”

“…T1D, a chronic autoimmune disorder, is characterized by insulin deficiency and resultant hyperglycaemia 277–279 . The complex interactions between the pancreatic β‐cell and innate and adaptive immune systems lead to the progression of T1D 280 .…”

Role of T follicular helper and T follicular regulatory cells in antibody-mediated rejection: new therapeutic targets?

“…Blimp1 expression in Tfr was shown to be abundant in tumour tissue and associated with an increased risk of melanoma metastasis, suggesting that it may be a key mechanism for tumour cell immune evasion [22]. In clinical patients with type 1 diabetes, Tfr cells are reduced in the spleen and pancreatic lymph nodes, and restoration of Tfr cells by adoptive transfer in animal models slowed disease progression [23]. In addition, Tfr may regulate lymphangiogenesis and lipoprotein metabolism during atherogenesis by targeting Tfh and regulatory B cells [24].…”