Here, we found that GFP-FoxP3<sup>+</sup> knock-in (KI) mice showed alterations in the production of anti-nuclear autoantibodies (ANAs) and nephritis with different extent, depending on the presence or absence of lupus susceptibility gene locus 1 (<i>Sle1</i>) and KI method: contrasting with B6.<i>Sle1</i>.fGFP-FoxP3 mice, expressing GFP via N-terminal insertion, B6.<i>Sle1</i>.iGFP-FoxP3, expressing GFP via bicistronic internal ribosome entry site-driven promotion, exhibited significantly lower penetrance of serum ANA, comparing to control B6.<i>Sle1</i> mice.
The human miR-34a, increased in peripheral blood mononuclear cells (PBMCs) and CD4<sup>+</sup> T cells from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients, displayed a positive correlation with some serum markers of inflammation including rheumatoid factor (RF), anti-streptolysin antibody (ASO), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as Th17 signature gene RORγt, but inversely correlated with the mRNA expression levels of FOXP3.
We previously reported that ex vivo TGF-β and IL-2-induced CD8+CD103+ regulatory T cells (CD8+CD103+ iTregs) displayed similar immunosuppressive effect and therapeutic function on lupus mice nephritis to that of CD4+Foxp3+ Tregs.
Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs.
The frequency of Th17 and Treg cells, the expression of IL-17A among Th17 cell, the plasma level of IL-17A, the expression of RORγt and FoxP3 genes were all significantly higher in SLE patients.
Our results suggest that the hCDR1-induced FOXP3 expressing regulatory T cells in lupus are not driven by IDO but rather by other hCDR1 regulated pathways.
Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4<sup>+</sup> T cell subsets but not in the aT<sub>reg</sub> subset, which was significantly decreased in patients with SLE.
We found that FOXP3 TSDR to have the highest mean melting temperature (highly methylated) in active SLE patients compared to all the other groups (p < 0.001).
FoxP3(+) cells were depleted within CD4(+)CD25(+) Tregs in patients with APS (28.4%) relative to those without APS (46.3%, p = 0.008). mTOR activity was similar between SLE patients with and without APS.
The level of Ets-1 and FOXP3 mRNA was not significantly different in hyperactive and lower active SLE group when compared with inactive SLE group, respectively (P > 0.05).
Our data suggest that Helios-expressing Foxp3(+) Treg with functional suppressive capacity and migratory potential into inflamed tissues are expanded in active SLE, presumably through γ-chain signalling cytokines and TCR stimulation, to compensate for autoreactive effector responses.
Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels.
The SLE Disease Activity Index (SLEDAI) score at the time of flare significantly correlated with the change in urinary level of IL-17 (r=-0.462, p=0.046) and GATA-3 (r=-0.455, p=0.05), but not MCP-1 or FOXP3, prior to the flare.
Although the exact role of Foxp3 and FOXP3 gene variations in SLE is still not clear, the present data support the importance of variations in the FOXP3 gene region for the etiology of certain manifestations of SLE.
Decreased mRNA expression of two FOXP3 isoforms in peripheral blood mononuclear cells from patients with rheumatoid arthritis and systemic lupus erythematosus.
In addition, healthy pDCs + apoPMNs induced suppressive T regulatory cell features with increased Foxp3 expression in CD4 + CD25 + cells while SLE pDCs + apoPMNs did not.
Treg frequency is highly heritable within SLE families, with specific variants of the CTLA4 and TGFbeta genes contributing to this trait, while FOXP3 contributes to SLE through mechanisms not involving a modulation of Treg frequency.
We found that the expression level of FOXP3 was significantly higher in urine from patients with active LN than from subjects with inactive lupus and healthy controls (24.5 +/- 45.8 vs 0.8 +/- 1.0 vs 0.6 +/- 0.8 copy; P < 0.001).
Among several proposed surface or intracellular Treg cell markers, CD25 at high level of expression and the transcription factor Foxp3 are the two most investigated in SLE.
However, the expression of TIM-3 ligand, galectin-9 increased in SLE patients indicating an enhanced engagement of TIM-3 with its ligand in SLE, which may result in a decreased regulatory T-cell function as shown by the decreased expression of FoxP3 and TGF-beta1 in SLE.
On the other hand and very interestingly, there are PIDs systematically associated with several autoimmune manifestations in which SLE has not been described, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), and autoimmune lymphoproliferative syndrome (ALPS), suggesting that mechanisms considered as critical players for induction and maintenance of tolerance to autoantigens, such as (1) AIRE-mediated thymic negative selection of lymphocytes, (2) Foxp3+ regulatory T cell-mediated peripheral tolerance, and (3) deletion of auto-reactive lymphocytes by Fas-mediated apoptosis, could not be relevant in SLE physiopathology.