IFN-? and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis - 06/06/19
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Abstract |
Background |
Inflammatory activation of CD8+ T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8+ T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder.
Objective |
The mechanism linking CD8+ T-cell hyperactivation to pathology is controversial, with excessive production of IFN-γ and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH.
Methods |
In addition to reporting a complete autosomal recessive IFN-γ receptor 1–deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1)KO mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-γ production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement.
Results |
We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8+ T cell–mediated pathology. The hematologic features of HLH were completely dependent on IFN-γ production, with complete correction after loss of IFN-γ production without any role for CD8+ T cell–mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-γ production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8+ T cells. These results were complemented by the characterization of an IFN-γ receptor 1–deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-γ signaling.
Conclusion |
These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8+ T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : IFN-γ, CD25, CD8+ T-cell hyperactivation, hemophagocytic lymphohistiocytosis
Abbreviations used : AR, DKO, EBV-B cell, HLH, IFN-γR1, JAK, LCMV, NK, sCD25, STAT, Treg
Plan
Supported by the VIB Grand Challenges, FWO, and IUAP (T-TIME). S.H-B. was supported by an FWO postdoctoral fellowship. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation, the Jeffrey Modell Foundation, the Rockefeller University Center for Clinical and Translational Science, grant no. 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grant no. 5R01AI089970-02), the Rockefeller University, the European Research Council (ERC), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), and the French National Research Agency (ANR) under the “Investments for the future” program (grant no. ANR-10-IAHU-01 and ANR-GENMSMD (ANR-16-CE17-0005-01). |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2215 - juin 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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