Human natural regulatory T cells (nTreg) recognize conserved peptides derived from the heavy constant region of IgG (Fc). The fine specificity of nTreg and the immunodominance of peptides was determined in healthy donors and rheumatoid arthritis (RA) patients. Eight Fc peptides were identified as highly immunogenic in all subjects with similar ranking and four of eight bound multiple class II HLA alleles. These Fc peptides are presented by IgG+ B cells by internalization and processing of surface IgG and are recognized by Fc-specific nTreg from both healthy donors and RA patients. However, exogenous IgG processed by antigen presenting cells (APC) led to the expansion of this nTreg population only in healthy donors. While nTreg from patients with RA responded to Fc peptides, the response to exogenous IgG presented by APC was compromised. These results demonstrate a hole in the central adaptive immune regulation in RA.