Rheumatoid arthritis develops in association with a defect in peripheral CD4 + T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4 + T cell clonal anergy induction. We therefore explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4 +T cells in the setting of selective T cell lymphopenia. CD4 + T cell recognition of self-GPI peptide/MHC class II complexes in normal murine hosts did not lead to arthritis and instead caused those T cells to develop a Folate receptor 4 hiCD73 hi anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3 +CD4 + regulatory T cells could not make GPI-specific CD4 +T cells anergic and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3 +CD4 + regulatory T cells are insufficient to functionally inactivate all autoreactive CD4 + T cells that encounter self-Ag.