Expression of the Autoimmune Susceptibility Gene FcRL3 on Human Regulatory T Cells Is Associated with Dysfunction and High Levels of Programmed Cell Death-1

CD4(+)FoxP3(+) regulatory T cells (T-reg) play a critical role in maintaining self-tolerance and inhibiting autoimmune disease. Despite being a major focus of modern immunological investigation, many aspects of T-reg biology remain unknown. In a screen for novel candidate genes involved in human T-reg function, we detected the expression of an autoimmune susceptibility gene, FcRL3, in T-reg but not in conventional CD4(+) T cells. FcRL3 is an orphan receptor of unknown function with structural homology to classical Fc receptors. Numerous genetic studies have demonstrated a link between a single nucleotide polymorphism, in the FCRL3 promoter and both overexpression of FcRL3 and autoimmune diseases such as rheumatoid arthritis. Given the critical role of T-reg in suppressing autoimmunity, we sought to ascertain how expression of FcRL3 relates to the phenotype, differentiation, and function of T-reg. We show in this study that FcRL3 is expressed on a population of thymically derived T-reg that exhibits a memory phenotype and high levels of programmed cell death-1. Purified FcRL3(+) T-reg are less responsive to antigenic stimulation in the presence of IL-2 than their FcRL3(-) counterparts, despite intact proximal and distal IL-2 signaling as determined by phosphorylation of Stat-5 and upregulation of Bcl2. In vitro suppression assays demonstrated that FcRL3(+) T-reg have reduced capacity to suppress the proliferation of effector T cells. These data suggest that FcRL3 expression is associated with T-reg dysfunction that may, in turn, contribute to the loss of self-tolerance and the development of autoimmunity. The Journal of Immunology, 2010, 184: 3639-3647.