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

Abstract

SummaryForkhead box P3 (FoxP3)+ regulatory T cells (Tregs) 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 Treg phenotype, we studied its role through developmentally defined regulatory T cell (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 differed sharply in their activated Treg CD25 state: while relatives as control subjects up‐regulated CD25 strongly in these cells during differentiation from naive Tregs, 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 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 up‐regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg‐directed therapies can be monitored more effectively when taking this distinction into account.

Targeting Regulatory T Cells to Treat Patients With Systemic Lupus Erythematosus

“…Considering that IL-2 production by T cells from SLE patients is impaired, it appears that this deficiency does not influence the numbers of Tregs in SLE. However, recent studies described that CD25 expression levels on the surface of Tregs were decreased in SLE patients ( 59 ). The reduction of CD25 expression in Tregs from patients with SLE correlated with the production of IL-2 by memory T cells indicating that deficiency of IL-2 in SLE patients reflects CD25 reduction in Tregs.…”

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

“…Suppressor of cytokine signaling 1 inhibition is important in the pathogenesis of SLE through the promotion of Treg cells plasticity ( 44 ). Dysregulation of Treg cells is highly implicated in the pathogenesis of SLE ( 45 ). T cell activation and autoantibody expression are accelerated in Treg cell-depleted lupus-prone mice ( 46 ).…”

Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

“…For example, individuals with Th1 deficiency are predisposed to recurrent bacterial and mycobacterial infections, and individuals with Th17 deficiency are predisposed to chronic mucocandidiasis [4][5][6] . In contrast, systemic autoimmunity is more common in individuals with Th17 overactivity and/or regulatory T cell (Treg) deficiency [7][8][9][10] , and allergy is more common in individuals with a similar imbalance between Th2 cells and Tregs [11][12][13] .…”

“…For example, individuals with Th1 deficiency are predisposed to recurrent bacterial and mycobacterial infections, and individuals with Th17 deficiency are predisposed to chronic mucocandidiasis ( McDonald, 2012 ; Cook and Tangye, 2009 ; Hernández-Santos et al, 2013 ). In contrast, systemic autoimmunity is more common in individuals with Th17 overactivity and/or regulatory T-cell (Treg) deficiency ( Osnes et al, 2013 ; Costa et al, 2017 ; Bonelli et al, 2008 ; Miyara et al, 2005 ), and allergy is more common in individuals with a similar imbalance between Th2 cells and Tregs ( Bacher and Scheffold, 2018 ; McGee and Agrawal, 2006 ; Finotto, 2008 ). Pathogenic and protective roles have also been described for Th9 and Th22 cells in the context of inflammatory skin diseases and various autoimmune conditions, including type I diabetes ( Ryba-Stanisławowska et al, 2016 ) and multiple sclerosis ( Rolla et al, 2014 ).…”