Stéphanie Humblet-Baron1, Dean Franckaert1, James Dooley1, Simon Bornschein1, Bénédicte Cauwe1, Susann Schönefeldt1, Xavier Bossuyt2, Patrick Matthys3, Frédéric Baron4, Carine Wouters5, Adrian Liston6. 1. Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium. 2. Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium. 3. Rega Institute, KUL-University of Leuven, Leuven, Belgium. 4. GIGA I(3) and the Department of Hematology, University of Liège, Liege, Belgium. 5. University Hospitals Leuven, Leuven, Belgium; Pediatric Immunology, KUL-University of Leuven, Leuven, Belgium. 6. Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KUL-University of Leuven, Leuven, Belgium. Electronic address: adrian.liston@vib.be.
Abstract
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-γ 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.
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-γ 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 FHLmouse 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.
Authors: E Brisse; M Imbrechts; T Mitera; J Vandenhaute; N Berghmans; L Boon; C Wouters; R Snoeck; G Andrei; P Matthys Journal: Clin Exp Immunol Date: 2018-01-18 Impact factor: 4.330
Authors: Naval Daver; Kenneth McClain; Carl E Allen; Sameer A Parikh; Zaher Otrock; Cristhiam Rojas-Hernandez; Boris Blechacz; Sa Wang; Milen Minkov; Michael B Jordan; Paul La Rosée; Hagop M Kantarjian Journal: Cancer Date: 2017-06-16 Impact factor: 6.860
Authors: Kent J Weinhold; Jack F Bukowski; Todd V Brennan; Robert J Noveck; Janet S Staats; Liwen Lin; Linda Stempora; Constance Hammond; Ann Wouters; Christopher F Mojcik; John Cheng; Mark Collinge; Michael I Jesson; Anasuya Hazra; Pinaki Biswas; Shuping Lan; James D Clark; Jennifer A Hodge Journal: Clin Immunol Date: 2018-03-05 Impact factor: 3.969
Authors: Carly E Whyte; Kailash Singh; James Dooley; Oliver T Burton; Meryem Aloulou; Lubna Kouser; Rafael Valente Veiga; Amy Dashwood; Hanneke Okkenhaug; Samira Benadda; Alena Moudra; Orian Bricard; Stephanie Lienart; Pascal Bielefeld; Carlos P Roca; Francisco José Naranjo-Galindo; Félix Lombard-Vadnais; Steffie Junius; David Bending; Masahiro Ono; Tino Hochepied; Timotheus Y F Halim; Susan Schlenner; Sylvie Lesage; Adrian Liston Journal: J Exp Med Date: 2022-06-14 Impact factor: 17.579