Excessive Anti-Viral CD8 T Cell Activation Inverts the IL-2 Consumptive Hierarchy Triggering Regulatory T Cell Collapse in Mouse Model for Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8⁺ T cell activation. HLH occurs in both acquired and familial (FHL) forms, with mutations in Perforin being a common cause of FHL. In both conditions a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent advances using experimental FHL triggered by lymphocytic choriomeningitis virus (LCMV) in Perforin-deficient mice have attributed the key distal event to be excessive IFNγ production, however the proximal events driving immune dysregulation have remained undefined. We investigated the role of regulatory T cells (Tregs) in the pathophysiology of experimental FHL. While we found no primary Treg defects in Perforin-deficient mice, Treg numbers collapsed following LCMV inoculation. The collapse of Treg numbers in LCMV-triggered Perforin-deficient, but not wildtype, mice was driven 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 sCD25 (IL-2 receptor). Together, these data demonstrate that excessive CD8+ T cell activation rewires the IL-2 homeostatic network away from Treg maintenance and towards feed-forward inflammation. In addition, reduced Treg number may contribute to the massive inflammation found in FHL.