Two separate effects contribute to regulatory T-cell defect in SLE patients and their unaffected relatives

Summary FOXP3+ regulatory T-cells (Tregs) are functionally deficient in Systemic Lupus Erythematosus (SLE), characterized by reduced surface CD25 (the 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 Treg phenotype, we studied its role through developmentally defined Treg 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 Treg 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 Tregs. This first component effect influenced the proportions of circulating CD4+FOXP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives sharply differed in their activated Tregs' CD25 state: while relatives as control subjects strongly upregulated CD25 in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 upregulation depended on IL2RA genetic variation and was functionally related to the proliferation of activated Tregs, 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 Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 upregulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg-directed therapies can be better monitored when taking this distinction into account. This article is protected by copyright. All rights reserved.