Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

Pierson, Wim; Cauwe, Bénédicte; Policheni, Antonia N.; Schlenner, Susan; Franckaert, Dean; Berges, Julien; Humblet-Baron, Stéphanie; Schönefeldt, Susann; Herold, Marco J.; Hildeman, David A.; Strasser, Andreas; Bouillet, Philippe; Lu, Li-Fan; Matthys, Patrick; Freitas, António A.; Luther, Rita J.; Weaver, Casey T.; Dooley, James; Liston, Adrian

doi:10.1038/ni.2649

Cited by 210 publications

(218 citation statements)

References 58 publications

(63 reference statements)

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“…21 Analysis of mean fluorescence expression of CD25 on Treg cells in lymph nodes after infection showed a significant reduction of CD25 expression in Prf1 2/2 mice compared with that seen in wild-type mice, strongly supporting the hypothesis of a lack of access to IL-2 for the Prf1 2/2 Treg cells (Fig 3, C). By contrast, splenic Treg cells did not demonstrate reduced CD25 expression (see Fig E3, B); however, Mcl1 expression downstream of IL-2 signaling in Treg cells was reduced in LCMV-infected Prf1 2/2 Treg cells (Fig 3, D), which is consistent with the role of IL-2 in maintaining the prosurvival Mcl1, 19 providing a potential mechanistic explanation for the observed death of Treg cells.…”

Section: Lcmv Infection In Perforin-deficient Mice Disrupts Il-2 Conssupporting

confidence: 62%

“…Because it has previously been demonstrated that IL-2 is required for optimal Foxp3 expression, 17 CD103 upregulation, 18 and Treg cell proliferation, 19 these results together suggest an impairment of the Treg-IL-2 homeostatic network. Together, these data demonstrate that an acquired peripheral Treg cell homeostasis defect develops in LCMV-infected Prf1 2/2 mice, but not wild-type mice, coincident with the hyperinflammatory state of HLH.…”

Section: Defective Treg Cell Homeostasis During Hlhmentioning

confidence: 73%

“…This hierarchy for consumption not only allows IL-2 to function as a rheostat for Treg cell numbers 19,20 but is also a proposed mechanism for Treg cell suppression of effector T cells. 23 We investigated whether this A-C, Expression of CD69 (Fig 2, A), CTLA4 (Fig 2, B), and CD103 (Fig 2, C) consumption hierarchy remained intact during the IL-2-deprived inflammatory environment of murine HLH.…”

Section: Lcmv Infection In Perforin-deficient Mice Disrupts Il-2 Consmentioning

confidence: 99%

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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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Section: Lcmv Infection In Perforin-deficient Mice Disrupts Il-2 Conssupporting

confidence: 62%

Section: Defective Treg Cell Homeostasis During Hlhmentioning

confidence: 73%

Section: Lcmv Infection In Perforin-deficient Mice Disrupts Il-2 Consmentioning

confidence: 99%

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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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“…Therefore, a platform of antigen-presenting cells does not obligate direct T reg -T eff cell interaction. In addition, recent evidence also suggested that niche-filling homeostasis of T reg cells may occur independently of DCs (Pierson et al, 2013). Nevertheless, our observations do not deemphasize the role of DCs in initiation and progression of immune damage.…”

Section: Ar Ticlecontrasting

confidence: 36%

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Jason¹,

Abdulreda²,

Devarajan³

et al. 2014

J Cell Biol

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Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell-mediated damage and protection of pancreatic islet grafts. Both CD4 + and CD8 + effector T (T eff ) lymphocytes directly engaged target cells. Strikingly, juxtaposed  cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3 + regulatory T (T reg ) cells persistently contacted T eff cells with or without involvement of CD11c + dendritic cells, an observation conciliating with the in vitro "trademark" of T reg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings.

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“…2). In particular, the altered cytokine environment in severe lymphopenia where there are high amount of IL-7 and IL-15 and relative deficiency of interleukin-2 (IL-2) could hamper the favorable reconstitution of Treg, since IL-2 is the essential cytokine regulating Treg homeostasis [8,[10][11][12]. IL-2 is a kind of old cytokine and high-dose IL-2 administration has been used to stimulate activated T and NK cells for the purpose of enhancing anti-tumor immunity [13,14].…”

Section: Introductionmentioning

confidence: 99%

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

Matsuoka

2017

Int J Hematol

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CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

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Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

Cited by 210 publications

References 58 publications

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

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

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

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