Arthritogenic self-reactive CD4 ⁺ T cells acquire an FR4 ^hiCD73 ^hi anergic state in the presence of foxp3 ⁺ regulatory t cells

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.