Homeostatic proliferation in the mice with germline FoxP3 mutation and its contribution to fatal autoimmunity.
FoxP3 has emerged as a critical regulator for the development and function of regulatory T cells. Recent studies by several groups have demonstrated that FoxP3 is expressed outside T cell lineages. In this context, we have reported that germline mutation of FoxP3 caused defective thymopoiesis, although its potential contribution to autoimmune diseases has not been analyzed. In this study, we report that, during perinatal period, germline mutation of FoxP3 in scurfy mice caused lymphopenia in the spleen and massive homeostatic proliferation, characterized by the independence from cognate Ags and expression of bona fide markers for homeostatic proliferation. The homeostatic proliferation is suppressed by increases in T cell numbers but not by adoptive transfer of regulatory T cells (Treg). Adoptive transfer of Treg-containing bulk T cells was dramatically more effective than transfer of either Treg alone or Treg-depleted CD4 T cells in curing the scurfy mice. Our data demonstrated that FoxP3 mutation not only ablates Treg, but also dramatically increased homeostatic proliferation during the perinatal period. Homeostatic proliferation acts in concert with Treg defects in causing acute and fatal autoimmune diseases in the FoxP3 mutant mice. These results demonstrated that germline mutation of FoxP3 caused two defects that work in concert to cause lethal autoimmunity.
Chang
Xing
X
Division of Immunotherapy, Section of General Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Zheng
Pan
P
Liu
Yang
Y
D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology; D018095:Germ-Line Mutation; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D051858:Forkhead Transcription Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; C498833:Foxp3 protein, mouse; C524056:Erbb2 protein, mouse