Date Published: January 16, 2019
Publisher: Public Library of Science
Author(s): Marsha Pellegrino, Antonino Crinò, Manuela M. Rosado, Alessandra Fierabracci, Keun Seok Seo.
Type 1 diabetes is an autoimmune disease where autoreactive T lymphocytes destroy pancreatic beta cells. We previously reported a defect in CD4+ Tregs cell proliferation and reduced CD4+ Tregs PD-1 expression in patients. Another ‘memory-like’ regulatory subset, CD8+ Tregs, evaluated as CD8+CD25+FOXP3+, has recently raised interest for their effective suppressive activity. Different CD8+ T cell populations, their proliferation capacity and expression of PD-1 molecule were evaluated by flow-cytometer analysis in newly diagnosed, long-term Type 1 diabetes patients compared to healthy normal donors. Under basal conditions, CD8+ Tregs and CD8+ Teffs were seemingly represented among study groups while there was evidence of diminished expression of PD-1 in Teff subsets of long-term patients. After 3 days of PMA/ionomycin stimulation, patients CD8+ Tregs showed decreased percentage in respect to control group. CD8+ Teffs were instead increased in long-term diabetics versus controls. PD-1+CD8+ Tregs were represented at a much lower percentage in long-term diabetic patients, in respect to controls. Importantly, patients CD8+ Tregs and CD8+ Teffs presented a significant proliferation defect in respect to the control group. In conclusion, our study indicates that a defect of CD8+ Tregs is observed in diabetics. This subset could thus represent a novel target of immunotherapy in patients.
Insulin-dependent diabetes mellitus (Type 1 diabetes, T1D) is due to the autoimmune destruction of insulin producing pancreatic islet beta cells by autoreactive effector T lymphocytes [1, 2]. Within its multifactorial pathogenesis, a close interaction of genetic background and environmental agents plays a major role. Establishment of thymic central tolerance in the perinatal age leads to elimination of autoreactive clones. Nevertheless, autoreactive T cells escape to thymic deletion and survive in the circulating peripheral blood (reviewed (rev) in [3, 2]); this implies that the immune system homeostasis is also contributed by peripheral tolerance. Thus, both altered central and peripheral tolerance mechanisms affect the onset and progression of the clinical disease; in particular this implies an altered function of T regulatory cells (Tregs) that play a fundamental role in controlling host immunity to self- or non-self-proteins and infectious agents [2,4].
Tregs are known to counteract autoreactive T cells and induce immune tolerance, through dampening inflammation. Regulatory mechanisms beyond their effects on T, B, natural killer (NK) and NKT cells are cell-to-cell-contact, secretion of immunosuppressive cytokines, effects on APCs, and competition for growth factors.