Immune Regulatory Functions of IgG in the Ontogeny of Human Natural Regulatory T Cells

Abstract

The heavy constant region of IgG (Fc) is highly immunogenic for human natural regulatory T cells (nTreg). Mature IgG+ B cells prime Fc-specific Treg via recycling of surface immunoglobulin with an antigen-processing pathway that is very efficient in presenting immunodominant Fc peptides to Treg. Some of these peptides are pan-HLA binders, explaining the presence of Fc-specific Treg in circulation in healthy pediatric and adult subjects. Following IgG+ B cell priming, further Treg expansion occurs with the presentation of Fc peptides following IgG uptake and processing by CD14+ myeloid dendritic cells type 2 (cDC2) and CD4+ immunoglobulin-like transcript 4 (ILT-4+) tolerogenic DC that secretes IL-10 when stimulated by the Fc that enters cells prevalently via Fcg receptor II. Fc-specific Treg are important in regulating naive T cell differentiation and account for a key mechanism of success for intravenous immunoglobulin therapy (IVIG) in several inflammatory conditions, including Kawasaki disease (KD) a pediatric acute vasculitis of the coronary arteries.