Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

Tian, Lei; Humblet-Baron, Stéphanie; Liston, Adrian

doi:10.1002/bies.201100180

Cited by 16 publications

(10 citation statements)

References 45 publications

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“…Different subsets of Tregs can mediate suppression in different ways, depending on the microenvironment. For example, IL-10 is particularly associated with Tregs that suppress Th17 proliferation (Tian et al ., 2012). Whether the observed increase in IL-10 secretion by Tregs from old mice indicates a shift in Treg subset populations as part of the aging process, is an intriguing question that remains to be examined.…”

Section: Discussionmentioning

confidence: 99%

Aging is associated with increased regulatory T‐cell function

Garg¹,

Delaney²,

et al. 2014

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Regulatory T-cell (Treg, CD4+CD25+) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T-cell responses. FoxP3 is a master regulator of Treg function, and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3–4 months) and aged (18–20 months) C57BL/6 mice. DNA from CD4+ T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T-cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling–mediated suppression of Teff proliferation during coculture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T-cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age.

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Section: Discussionmentioning

confidence: 99%

Aging is associated with increased regulatory T‐cell function

Garg¹,

Delaney²,

et al. 2014

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“…Treg cells from Prf1 2/2 mice infected with LCMV, by contrast, showed greater levels of activation, with a sustained upregulation of CD69 (Fig 2, A) and CTLA4 (Fig 2, B) that is consistent with the activation of Treg cells by inflammatory environments. 16 Paradoxically, expression of Foxp3 and CD103 was reduced on Treg cells from Prf1 2/2 mice in comparison with those from wild-type mice (Fig 2, C and D), and proliferation of Treg cells in the lymph nodes of Prf1 2/2 mice was dampened (Fig 2, E). Similar results were observed in the spleen (see Fig E2 in this article's Online Repository at www.jacionline.org).…”

Section: Defective Treg Cell Homeostasis During Hlhmentioning

confidence: 94%

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

Humblet-Baron

Franckaert

Dooley

et al. 2016

Journal of Allergy and Clinical Immunology

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Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8 1 T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and lifethreatening. Recent studies have attributed the key distal event to excessive IFN-g production; however, the proximal events driving immune dysregulation have remained undefined. Objective: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. Methods: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8 1 T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode. Results: We found no primary Treg cell defects in perforindeficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4 1 T cells, increased IL-2 consumption by activated CD8 1 T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares. Conclusion: These results demonstrate that excessive CD8 1 T-cell activation rewires the IL-2 homeostatic network away

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“…Frequently the transcriptional profile of a given Treg subset is reported to parallel that of the effector T cell subset targeted for control [126]. While there are other ways to interpret these data [127], at face value the message is that Treg are not a homogenous population. It follows that different subsets of Treg could employ particular suppressive mechanisms to differing extents.…”

Section: Overall Perspectivesmentioning

confidence: 99%

Treg and CTLA-4: Two intertwining pathways to immune tolerance

Walker

2013

Journal of Autoimmunity

349

251

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Both the CTLA-4 pathway and regulatory T cells (Treg) are essential for the control of immune homeostasis. Their therapeutic relevance is highlighted by the increasing use of anti-CTLA-4 antibody in tumor therapy and the development of Treg cell transfer strategies for use in autoimmunity and transplantation settings. The CTLA-4 pathway first came to the attention of the immunological community in 1995 with the discovery that mice deficient in Ctla-4 suffered a fatal lymphoproliferative syndrome. Eight years later, mice lacking the critical Treg transcription factor Foxp3 were shown to exhibit a remarkably similar phenotype. Much of the debate since has centered on the question of whether Treg suppressive function requires CTLA-4. The finding that it does in some settings but not in others has provoked controversy and inevitable polarization of opinion. In this article, I suggest that CTLA-4 and Treg represent complementary and largely overlapping mechanisms of immune tolerance. I argue that Treg commonly use CTLA-4 to effect suppression, however CTLA-4 can also function in the non-Treg compartment while Treg can invoke CTLA-4-independent mechanisms of suppression. The notion that Foxp3 and CTLA-4 direct independent programs of immune regulation, which in practice overlap to a significant extent, will hopefully help move us towards a better appreciation of the underlying biology and therapeutic significance of these pathways.

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Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

Cited by 16 publications

References 45 publications

Aging is associated with increased regulatory T‐cell function

Aging is associated with increased regulatory T‐cell function

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

Treg and CTLA-4: Two intertwining pathways to immune tolerance

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