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.