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.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Lymph Nodes/pathology , Spleen/pathology , T-Lymphocytes, Regulatory/pathology , Adult , Animals , Case-Control Studies , Cells, Cultured , Diabetes Mellitus, Type 1/pathology , Humans , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , PancreasABSTRACT
Age-related reductions in vaccine-induced B cells in aging indicate that germinal centers (GCs), the anatomical site where the development of humoral responses takes place, may lose efficacy with age. We have investigated the baseline follicular and GC composition in nonhuman primates (NHPs) with respect to their age. There was a marked reduction in follicular area in old animals. We found significantly lower normalized numbers of follicular PD1hi CD4 T (Tfh) and proliferating (Ki67hi ) GC B cells with aging, a profile associated with significantly higher numbers of potential follicular suppressor FoxP3hi Lag3hi CD4 T cells. Furthermore, a positive correlation was found between Tfh and follicular CD8 T cells (fCD8) only in young animals. Despite the increased levels of circulating preinflammatory factors in aging, young animals had higher numbers of monocytes and granulocytes in the follicles, a profile negatively associated with numbers of Tfh cells. Multiple regression analysis showed an altered association between GC B cells and other GC immune cell populations in old animals suggesting a differential mechanistic regulation of GC activity in aging. Our data demonstrate defective baseline GC composition in old NHPs and provide an immunological base for further understanding the adaptive humoral responses with respect to aging.
