Homeostatic proliferation in the mice with germline FoxP3 mutation and its contribution to fatal autoimmunity

被引:25
作者
Chang, Xing [1 ]
Zheng, Pan [1 ,2 ]
Liu, Yang [1 ,3 ,4 ]
机构
[1] Univ Michigan, Ctr Med, Dept Surg, Div Immunotherapy,Sect Gen Surg, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Ctr Med, Dept Pathol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Ctr Med, Div Mol Med & Genet, Dept Internal Med & Pathol,Comprehens Canc Ctr, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Ctr Med, Program Mol Mech Dis, Ann Arbor, MI 48109 USA
关键词
D O I
10.4049/jimmunol.181.4.2399
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:2399 / 2406
页数:8
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