Regulatory T cell features in chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in any of the genes encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, responsible for the production of reactive oxygen species (ROS). CGD is marked by invasive bacterial and fungal infections and by autoinflammation/autoimmunity, of which the exact pathophysiology remains elusive. Contributing factors include decreased neutrophil apoptosis, impaired apoptotic neutrophil clearance, increased proinflammatory protein expression and reduced ROS-mediated inflammasome dampening. We have explored a fundamentally different potential mechanism: it has been reported that macrophage-mediated induction of regulatory T cells (T_regs ) depends on ROS production. We have investigated whether numerical or functional deficiencies exist in T_regs of CGD patients. As the prevalence of autoinflammation/autoimmunity differs between CGD subtypes, we have also investigated T_regs from gp91^phox -, p47^phox - and p40^phox -deficient CGD patients separately. Results show that T_reg numbers and suppressive capacities are not different in CGD patients compared to healthy controls, with the exception that in gp91^phox -deficiency effector T_reg (eT_reg ) numbers are decreased. Expression of T_reg markers CD25, inducible T cell co-stimulator (ICOS), Helios, cytotoxic T lymphocyte antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR) did not provide any clue for differences in T_reg functionality or activation state. No correlation was seen between eT_reg numbers and patients' clinical phenotype. To conclude, the only difference between T_regs from CGD patients and healthy controls is a decrease in circulating eT_regs in gp91^phox -deficiency. In terms of autoinflammation/autoimmunity, this group is the most affected. However, upon culture, patient-derived T_regs showed a normal phenotype and normal functional suppressor activity. No other findings pointed towards a role for T_regs in CGD-related autoinflammation/autoimmunity.

Keywords: chronic granulomatous disease; inflammation; regulatory T cell.