Article (Scientific journals)
IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.
Humblet-Baron, Stephanie; Franckaert, Dean; Dooley, James et al.
2016In Journal of Allergy and Clinical Immunology, 138 (1), p. 200-209.e8
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Keywords :
IL-2; Regulatory T cells; familial hemophagocytic lymphohistiocytosis; immune homeostasis; lymphocytic choriomeningitis virus; perforin
Abstract :
[en] BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) 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 life-threatening. Recent studies have attributed the key distal event to excessive IFN-gamma 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(+) 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 perforin-deficient 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(+) T cells, increased IL-2 consumption by activated CD8(+) 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(+) T-cell activation rewires the IL-2 homeostatic network away from Treg cell maintenance and toward feed-forward inflammation. These results also provide a potential mechanistic pathway for the progression of infectious inflammation to persistent inflammation in patients with HLH.
Disciplines :
Immunology & infectious disease
Author, co-author :
Humblet-Baron, Stephanie
Franckaert, Dean
Dooley, James
Bornschein, Simon
Cauwe, Benedicte
Schonefeldt, Susann
Bossuyt, Xavier
Matthys, Patrick
Baron, Frédéric  ;  Université de Liège > GIGA-R : Hématologie
Wouters, Carine
Liston, Adrian
Language :
English
Title :
IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.
Publication date :
2016
Journal title :
Journal of Allergy and Clinical Immunology
ISSN :
0091-6749
eISSN :
1097-6825
Publisher :
Mosby, United States - Missouri
Volume :
138
Issue :
1
Pages :
200-209.e8
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Available on ORBi :
since 09 July 2016

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