IFN-γ and CD25 drive distinct pathological features during hemophagocytic lymphohistiocytosis

Publication date: Available online 19 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Stéphanie Humblet-Baron, Dean Franckaert, James Dooley, Fatima Ailal, Aziz Bousfiha, Caroline Deswarte, Carmen Oleaga-Quintas, Jean-Laurent Casanova, Jacinta Bustamante, Adrian Liston

Abstract

Background

The inflammatory activation of CD8⁺ T cells can, when unchecked, drive severe immunopathology. Hyper-stimulation 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 hyper-activation to pathology is controversial, with excessive production of IFN-γ and, more recently, excessive consumption of IL-2, 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 IFN-γR1 deficient patient with multiple aspects of HLH pathology, we used the mouse model of Prf1^KO mice infected with LCMV to genetically eliminate either IFN-γ production or CD25 expression and assess the immunological, hematological and physiological disease measurement.

Results

We found a striking dichotomy between mechanistic basis of the hematological and inflammatory components of CD8⁺ T cell-mediated pathology. The hematological features of HLH were completely dependent on IFN-γ production, with complete correction following loss of IFN-γ production, without any role for CD8⁺ T cell-mediated IL-2 consumption. The mechanistic contribution of the immunological features, by contrast, were reversed, with no role for IFN-γ production, but substantial correction following the reduction of IL-2 consumption by hyper-activated CD8⁺ T cells. These results were complemented by the characterization of an IFN-γR1-deficient HLH-like patient, where multiple aspects of HLH pathology was 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 hyper-activation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.

Graphical abstract

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