Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their...

Forkhead box P3 (FoxP3)⁺ regulatory T cells (T_regs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE T_reg phenotype, we studied its role through developmentally defined regulatory T cell (T_reg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to T_reg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4⁺ FoxP3⁺ CD45RO^- CD31⁺ recent thymic emigrant T_regs . This first component effect influenced the proportions of circulating CD4⁺ FoxP3^high CD45RO⁺ activated T_regs . (2) In contrast, patients and unaffected relatives differed sharply in their activated T_reg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive T_regs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated T_regs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early T_regs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral T_reg activation that is selectively deficient in patients. We expect that T_reg -directed therapies can be monitored more effectively when taking this distinction into account.