Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

Hadaschik, Eva; Wei, Xiaoying; Leiss, Harald; Heckmann, Britta; Niederreiter, Birgit; Steiner, Günter; Walter, Ulrich; Enk, Alexander H.; Smolen, Josef S.; Stummvoll, Georg

doi:10.1186/s13075-015-0538-0

Cited by 57 publications

(58 citation statements)

References 53 publications

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“…We also discovered significantly elevated levels of ANAs in young cKO mice. This is of interest since it has lately been demonstrated that Treg-deficient scurfy mice are positive for ANAs and other autoantibodies and even develop systemic lupus erythematosus-like symptoms (39). Although CD83cKO mice did not develop spontaneous autoimmune disorders, deletion of CD83 on Tregs clearly resulted in a more highly activated, proinflammatory phenotype.…”

Section: Discussionmentioning

confidence: 99%

CD83 expression is essential for Treg cell differentiation and stability

Doebbeler¹,

Koenig²,

Krzyzak³

et al. 2018

JCI Insight

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Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.

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Section: Discussionmentioning

confidence: 99%

CD83 expression is essential for Treg cell differentiation and stability

Doebbeler¹,

Koenig²,

Krzyzak³

et al. 2018

JCI Insight

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“…Scurfy (Sf) mice with Treg abnormalities harbor a missense mutation in FOXP3 [ 6 ] and develop anti-dsDNA, anti-Smith, and antinuclear antibodies similar to those of SLE patients. Such FOXP3 mutant mice also exhibit multiorgan inflammation of systems usually involved in SLE [ 20 ]. However, when Tregs were defined as “FOXP3-positive” cells, the proportions of such cells did not differ between SLE patients and controls because the definitions of Tregs were complicated by the addition of CD25 status, giving “CD25-negative and FOXP3-positive” and “CD25 and FOXP3 double positive.” This phenomenon may be explained by the findings of other studies indicating that the CD4 + CD25 − FOXP3 + T cells of SLE were dysfunctional Tregs [ 21 , 22 ] and may even be previously activated conventional T cells [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The Proportion of Regulatory T Cells in Patients with Systemic Lupus Erythematosus: A Meta-Analysis

Zhang

et al. 2018

Journal of Immunology Research

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Background Accumulating evidence indicates that a deficiency in or dysfunction of regulatory T cells (Tregs) is involved in the pathogenesis of systemic lupus erythematosus (SLE). As different markers have been used to identify Tregs, recent studies on the proportions of Tregs in SLE patients have generated controversial results. To clarify the status of Tregs in such patients, we determined the proportions of Tregs present during development of the disease, with special consideration of controversial cellular markers. Methods We identified studies reporting the proportions of Tregs in SLE patients by searching relevant databases through March 2018. Using the PRISMA guidelines, we performed a random effects meta-analysis of the frequencies of Tregs defined in different ways. Inconsistency was evaluated using the I-squared index (I 2), and publication bias was assessed by examining funnel plot asymmetry using the Begger and Egger tests. Results Forty-four studies involving 2779 participants were included in the meta-analysis. No significant difference in the proportions of Tregs was evident between 1772 patients and 1007 controls [−0.191, (−0.552, 0.362), p = 0.613, I 2 = 95.7%]. We next conducted subanalyses based on individual definitions of Tregs. When the Treg definition included “FOXP3-positive” cells, the proportions did not differ between SLE patients and controls [−0.042, (−0.548, 0.632), p = 0.889, I 2 = 96.6%]; this was the case when Tregs were defined as either “CD25low/−FOXP3+” or “CD25high/+FOXP3+” cells. SLE patients had lower proportions of Tregs that were “single CD25-positive” [−1.428, (−1.982, −0.873), p < 0.001, I 2 = 93.4%] and “CD127-negative” [−1.093, (−2.002, −0.183), p = 0.018, I 2 = 92.6%] compared to controls. Tregs defined as “CD25bright,” “CD25bright/highCD127low/−,” and “CD25highCD127low/−FOXP3+” did not differ in proportion between SLE patients and controls. Conclusions The Treg proportions varied by the cellular identification method used. The proportions of Tregs that were accurately identified and functionally validated fell among patients with SLE. Stricter definitions of Tregs are necessary when evaluating the status of such patients.

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“…Since skin represents one of the largest barrier tissues, the prerequisite to protect itself from any unwanted damage and the subsequent persistent immune response is high; therefore, Tregs are an integral part of the microenvironmental control in maintaining skin homeostasis. In line with this hypothesis, scurfy mice, which harbor a missense mutation in the Foxp3 gene resulting in a lack of functional Tregs, have been reported to develop spontaneous autoimmune disorders including interface dermatitis …”

Section: Regulatory T Cellsmentioning

confidence: 89%

The lymphoid cell network in the skin

et al. 2018

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Cutaneous immunity represents a crucial component of the mammalian immune response. The presence of a large array of commensal microorganisms along with a myriad of environmental stresses necessitates constant immuno-surveillance of the tissue. To achieve a perfect balance between immune-tolerance and immune-activation, the skin harbors strategically localized immune cell populations that modulate these responses. To maintain homeostasis, innate and adaptive immune cells assimilate microenvironmental cues and coordinate cellular and molecular functions in a spatiotemporal manner. The role of lymphoid cells in cutaneous immunity is gaining much appreciation due to their important roles in regulating skin health and pathology. In this review, we aim to highlight the recent advances in the field of cutaneous lymphoid biology.

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Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

Cited by 57 publications

References 53 publications

CD83 expression is essential for Treg cell differentiation and stability

CD83 expression is essential for Treg cell differentiation and stability

The Proportion of Regulatory T Cells in Patients with Systemic Lupus Erythematosus: A Meta-Analysis

The lymphoid cell network in the skin

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