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Summary  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.

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