Immune deficiencies, infection, and systemic immune disorders
IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

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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.

Section snippets

Patients

Diagnostic data were obtained from patients with FHL/MAS during routine clinical care at UZ Leuven. Neonatal patients were excluded from analysis. Of the 7 patients identified during active FHL/MAS, 3 had not received any treatment related to an FHL/MAS episode at the time of the analysis, whereas 4 other patients had already started corticosteroids, cyclosporine treatment, or both. Written informed consent was obtained from each patient. The Ethics Committee of the University of Leuven and

Defective Treg cell homeostasis during HLH

To determine the proximal cause of uncontrolled inflammation in patients with FHL, we investigated the properties of Treg cells, one of the key regulators of immune activation. Perforin knockout (Prf1−/−) mice, with the same underlining genetic deficiency as patients with FHL, were used to assess Treg cell status. To investigate Treg cell homeostasis during inflammation in an FHL murine model, wild-type and Prf1−/− mice were treated with LCMV (Armstrong strain). After infection, wild-type mice

Discussion

In this report we describe the fate of Treg cells under the debilitating condition of LCMV-induced FHL. We demonstrated that after excessive activation of CD8+ T cells, IL-2 production is reduced and the consumption hierarchy is reversed, leading to preferential consumption by inflammatory CD8+ T cells to the detriment of anti-inflammatory Treg cells.

Under physiologic conditions, Treg cells are important actors in peripheral immune tolerance, creating a buffer against spontaneous immune

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    Supported by the VIB, ERC (-IMMUNO), FWO (G051912N) and IUAP (T-TIME). S.H.-B. and B.C. were supported by FWO postdoctoral fellowships.

    Disclosure of potential conflict of interest: S. Humblet-Baron receives research funding from FWO. J. Dooley receives research funding from FWO. B. Cauwe is an employee of ABBVIE as a Medical Science Liaison. F. Baron received payments from Genzyme and received travel support from Celgene, Genzyme, and Novartis. A. Liston receives research funding FWO and ERC. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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