The Role of the LAT-PLC-γ1 Interaction in T Regulatory Cell Function

被引:51
|
作者
Chuck, Mariana I. [1 ]
Zhu, Minghua [1 ]
Shen, Shudan [1 ]
Zhang, Weiguo [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA
来源
JOURNAL OF IMMUNOLOGY | 2010年 / 184卷 / 05期
关键词
RAS ACTIVATION; LYMPHOPROLIFERATIVE DISORDER; COSTIMULATORY MOLECULES; INTESTINAL INFLAMMATION; DEPENDENT MECHANISMS; ADAPTER PROTEIN; DENDRITIC CELLS; LAT; TOLERANCE; MUTATION;
D O I
10.4049/jimmunol.0902876
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The interaction between the linker for activation of T cells (LAT) with PLC-gamma 1 is important for TCR-mediated Ca2+ signaling and MAPK activation. Knock-in mice harboring a mutation at the PLC-gamma 1 binding site (Y136) of LAT develop a severe lymphoproliferative syndrome. These mice have defective thymic development and selection and lack natural regulatory T cells, implicating a breakdown of both central and peripheral tolerance. To bypass this developmental defect, we developed a conditional knock-in line in which only LATY136F is expressed in mature T cells after deletion of the wild type LAT allele. Analysis of LATY136F T cells indicated that the interaction between LAT and PLC-gamma 1 plays an important role in TCR-mediated signaling, proliferation, and IL-2 production. Furthermore, the deletion of LAT induced development of the lymphoproliferative syndrome in these mice. Although Foxp3(+) natural Treg cells were present in these mice after deletion, they were unable to suppress the proliferation of conventional T cells. Our data indicate that the binding of LAT to PLC-gamma 1 is essential for the suppressive function of CD(4+)CD25(+) regulatory T cells. The Journal of Immunology, 2010, 184: 2476-2486.
引用
收藏
页码:2476 / 2486
页数:11
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