IL-2R Signaling Is Essential for Functional Maturation of Regulatory T Cells during Thymic Development

Cheng, Guangcun; Yu, Aixin; Dee, Michael J.; Malek, Thomas R.

doi:10.4049/jimmunol.1201218

Cited by 88 publications

(88 citation statements)

References 40 publications

(61 reference statements)

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“…Furthermore, STAT5 binds to the conserved sites within the Foxp3 promoter, and then STAT5 signaling regulates Foxp3 expression (42,43). Our data showed that Socs1 expression in IL-2-stimulated Treg cells of RORgt Tg mice was significantly higher than in that of C57BL/6 mice.…”

Section: Foxp3supporting

confidence: 49%

A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

Iizuka

Tsuboi

Matsuo

et al. 2015

The Journal of Immunology

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The nuclear receptor retinoic acid–related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren’s syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4+ T cells. RORγt-overexpressing CD4+ T cells induced sialadenitis as a result of transferred CD4+ T cells from Tg mice into Rag2−/− mice. The examination of IL-17–deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4+CD25+Foxp3+ regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2−/− mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4+ T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.

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Section: Foxp3supporting

confidence: 49%

A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

Iizuka

Tsuboi

Matsuo

et al. 2015

The Journal of Immunology

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“…CD4 1 CD8 1 thymocytes interact with class II MHC-expressing cells in the medullar and Hassall's corpuscles of thymus, where thymic stromal lymphopoietin promotes myeloid and plasmacytoid dendritic cells that induce Tregs (75). Treg induction requires TGF-b, stimulation of CD28 by B7.2, and IL-2 activating the IL-2R to induce Stat5 and FOXP3 (76). FOXP3 induces CD25 and inhibits IL-2 expression.…”

Section: Professional Spies-tregsmentioning

confidence: 99%

T Cells

Hall

2015

Clinical Journal of the American Society of Nephrology

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Traditionally, T cells were CD4 1 helper or CD8 1 cytotoxic T cells, and with antibodies, they were the soldiers of immunity. Now, many functionally distinct subsets of activated CD4 1 and CD8 1 T cells have been described, each with distinct cytokine and transcription factor expression. For CD4 1 T cells, these include Th1 cells expressing the transcription factor T-bet and cytokines IL-2, IFN-g, and TNF-b; Th2 cells expressing GATA-3 and the cytokines IL-4, IL-5, and IL-13; and Th17 cells expressing RORgt and cytokines IL-17A, IL-17F, IL-21, and IL-22. The cytokines produced determine the immune inflammation that they mediate. T cells of the effector lineage can be naïve T cells, recently activated T cells, or memory T cells that can be distinguished by cell surface markers. T regulatory cells or spies were characterized as CD8 1 T cells expressing I-J in the 1970s. In the 1980s, suppressor cells fell into disrepute when the gene for I-J was not present in the mouse MHC I region. At that time, a CD4 1 T cell expressing CD25, the IL-2 receptor-a, was identified to transfer transplant tolerance. This was the same phenotype of activated CD4 1 CD25 1 T cells that mediated rejection. Thus, the cells that could induce tolerance and undermine rejection had similar badges and uniforms as the cells effecting rejection. Later, FOXP3, a transcription factor that confers suppressor function, was described and distinguishes T regulatory cells from effector T cells. Many subtypes of T regulatory cells can be characterized by different expressions of cytokines and receptors for cytokines or chemokines. In intense immune inflammation, T regulatory cells express cytokines characteristic of effector cells; for example, Th1-like T regulatory cells express T-bet, and IFN-g-like Th1 cells and effector T cells can change sides by converting to T regulatory cells. Effector T cells and T regulatory cells use similar molecules to be activated and mediate their function, and thus, it can be very difficult to distinguish soldiers from spies.

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“…At the earliest stage of the development, IL-2 engagement in the thymus promotes expression of Foxp3 in developing CD4 + T cells, contributing to the development of mature and functional tTregs [29,63,64]. In the periphery, further IL-2/IL-2R interactions are required to maintain the competitive fitness of the tTreg pool [65–67].…”

Section: Il-2 and Treg Homeostasismentioning

confidence: 99%

“…Interestingly, some Foxp3-expressing cells are still detected in IL-2- and IL-2rα-deficient mice despite the lack of IL-2 signaling [65,66], most likely due to the redundant capacity of IL-7 and IL-15 to activate Stat5 and partially compensate for the absence of IL-2/IL-2R interactions [72,73]. However, these cells express lower levels of Foxp3 and other key Treg functional molecules, including CTLA-4, and demonstrate poor competitive fitness and function when compared with Tregs developing in wild-type animals [29,65,66]. This supports an essential and non-redundant role for IL-2 in promoting Treg homeostasis and function.…”

Section: Il-2 and Treg Homeostasismentioning

confidence: 99%

“…More Importantly and contrary to what was initially predicted, self-reactive T and B cells undergo uncontrolled expansion in IL-2- and IL-2 receptor-deficient mice, which develop a severe autoimmune syndrome [23–25]. Similarly, autoimmune disease development is linked to IL-2 deficiencies in humans [26–28], most likely due to the expansion of immature nonfunctional Tregs in the absence of IL-2 signals [29,30]. The close association between IL-2 deficiency and autoimmune disorders supports the important role of IL-2 in suppressing unwanted immune responses and maintaining immune tolerance.…”

mentioning

confidence: 99%

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Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Ballesteros-Tato¹

2014

Immunotherapy

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Low-dose IL-2 administration suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders. Increased Tregs activity is one of the potential mechanisms by which low-dose IL-2 immunotherapy induces immunosuppression. In addition, recent data indicate that IL-2 may contribute to prevent unwanted self-reactive responses by preventing the developing of T-follicular helper cells, a CD4+ T-cell subset that expands in autoimmune disease patients and promotes long-term effector B-cell responses. Here we discuss the mechanisms underlying the clinical benefits of low-dose IL-2 administration, focusing on the role of this cytokine in promoting Treg-mediated suppression and preventing self-reactive T-follicular helper cell responses.

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IL-2R Signaling Is Essential for Functional Maturation of Regulatory T Cells during Thymic Development

Cited by 88 publications

References 40 publications

A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

T Cells

Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

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