A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T cell checkpoint: Both IL-2 knockout and Fas mutation prolong lifespan of Scurfy mice but by different mechanisms

Mutation of the Foxp3 transcription factor in Scurfy (Sf) mice results in complete absence of the CD4(+)Foxp3(+) regulatory T cells (Tregs), severe multiorgan autoimmune syndrome, and early death at 4 wk of age. However, Sf mice simultaneously bearing the Il2(-/-) (Sf.Il2(-/-)) or Fas(lpr/lpr) gene (Sf.Fas(lpr/lpr)) have extended lifespan despite totally lacking Tregs, indicating a role of IL-2 and CD95 (Fas) signaling pathways in the multiorgan autoimmune syndrome beyond the Treg checkpoint. IL-2 has been implicated in regulating lymphoproliferation and CD178 (FasL) expression. However, Sf.Il2(-/-) mice have increased lymphoproliferation and FasL expression. Importantly, the pattern of organ-specific autoimmune response of Sf.Il2(-/-) mice resembled IL-2 knockout mice whereas that of Sf.Fas(lpr/lpr) was similar to Sf mice, indicating that the distinct and weakened autoimmune manifestation in IL-2 knockout mice was not caused by the residual Tregs. Our study demonstrated a novel role of IL-2 in regulating multiorgan autoimmune inflammation beyond the Treg checkpoint and indicated that both Il2(-/-) and Fas(lpr/lpr) genes prolong the lifespan of Sf mice but by different mechanisms.