IL-2 coordinates IL-2–producing and regulatory T cell interplay

Amado, Inês F.; Berges, Julien; Luther, Rita J.; Mailhe, Marie‐Pierre; Garcia, Sylvie; Bandeira, António; Weaver, Casey T.; Liston, Adrian; Freitas, António A.

doi:10.1084/jem.20122759

Cited by 87 publications

(82 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This process, termed quorum sensing, allows individual members of a community to exhibit collectivist behaviors in order to coordinate expression of energetically expensive processes involved in virulence and differentiation (71). While quorum sensing has been theorized to be relevant to understanding lymphocyte behavior (72,73), our data add to growing experimental data demonstrating that, under certain circumstances, T cells can also exhibit collectivist behaviors (74,75).…”

Section: Discussionmentioning

confidence: 70%

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Klebanoff¹,

Scott²,

Leonardi³

et al. 2015

Journal of Clinical Investigation

208

221

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 70%

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Klebanoff¹,

Scott²,

Leonardi³

et al. 2015

Journal of Clinical Investigation

208

221

View full text Add to dashboard Cite

“…IL-2 production by activated T cells is transient and transcriptionally regulated, including silencing by Blimp1 and Aiolos (encoded by Ikzf3) [18]. Moreover, negative feedback appears to also exist on the cellular level involving IL-2-producing CD4 + T and IL-2-consuming Treg cells [25]. Such regulation mechanisms might be key in preventing T cell overstimulation by persistent IL-2 signals in conjunction with repetitive TCR stimulation by antigen (including self-and tumor antigens), which can lead to T cell exhaustion or Fas (CD95)-mediated activation-induced cell death [26,27].…”

Section: The Biology Of Il-2mentioning

confidence: 99%

Interleukin-2: Biology, Design and Application

Arenas-Ramirez

Woytschak

Boyman

2015

Trends in Immunology

306

283

View full text Add to dashboard Cite

Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating antitumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation.

show abstract

“…Direct quantification of the low concentration of IL-2 present in mouse serum remains challenging. However, because the main source of IL-2 provision to Treg cells is CD4 1 T cells, 20 IL-2 production could be measured. By using intracellular cytokine staining, IL-2 secretion was consistently lower in CD4 1 T cells from infected Prf1 2/2 mice compared with wild-type mice (Fig 3, A).…”

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

confidence: 99%

“…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%

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

Self Cite

View full text Add to dashboard Cite

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

show abstract

IL-2 coordinates IL-2–producing and regulatory T cell interplay

Abstract: Regulation of IL-2–producing CD4+ T cell numbers is controlled by a quorum-sensing feedback loop as regulatory T cells sense the IL-2 produced.

Cited by 87 publications

References 56 publications

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Interleukin-2: Biology, Design and Application

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

Contact Info

Product

Resources

About