title: IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.
abstract: 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-γ production; however, the proximal events driving immune dysregulation have remained undefined.
  
  
  
  We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Dean
authors.initials: D
authors.lastname: Franckaert
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Bornschein
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Cauwe
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Susann
authors.initials: S
authors.lastname: Schönefeldt
authors.affiliation: Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bossuyt
authors.affiliation: Rega Institute, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
authors.affiliation: GIGA I(3) and the Department of Hematology, University of Liège, Liege, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.affiliation: University Hospitals Leuven, Leuven, Belgium; Pediatric Immunology, KUL-University of Leuven, Leuven, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium. Electronic address: adrian.liston@vib.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D056747:Immunomodulation; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D054353:Perforin
keywords: IL-2; Regulatory T cells; familial hemophagocytic lymphohistiocytosis; immune homeostasis; lymphocytic choriomeningitis virus; perforin