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 Faslpr/lpr gene (Sf.Faslpr/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.Faslpr/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 Faslpr/lpr genes prolong the lifespan of Sf mice but by different mechanisms.
Zheng
Lingjie
L
Department of Microbiology and Center of Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville 22908, USA.
Sharma
Rahul
R
Gaskin
Felicia
F
Fu
Shu Man
SM
Ju
Shyr-Te
ST
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology*; D008136:Longevity / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D019014:fas Receptor