A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity.
A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity.
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ZAP-70 的亚等位基因揭示了自身免疫性疾病与自身免疫反应性的不同胸腺阈值。
DOI：
10.1084/jem.20082902
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发表时间：
2009-10-26
期刊：
影响因子：
--
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Hsu LY;Tan YX;Xiao Z;Malissen M;Weiss A
ZAP-70对T细胞受体（TCR）信号传导至关重要。ZAP-70中Y315和Y319的酪氨酸到苯丙氨酸突变表明这些残基具有招募下游效应分子的功能，但诱变和结晶研究表明这些残基在ZAP-70的自抑制中也起重要作用。为了解决脚手架功能的重要性，我们产生了一个zap70突变小鼠（YYAA小鼠），其中Y315和Y319都突变为丙氨酸。这些YYAA小鼠揭示了支架功能对正常发育和功能的重要作用。此外，YYAA小鼠与先前鉴定的ZAP-70突变小鼠SKG有许多相似之处，后者具有明显的半形态突变。YYAA和SKG小鼠都有T细胞发育受损和对TCR刺激反应低下，胸腺T调节细胞数量明显减少，阳性和阴性选择缺陷。YYAA小鼠和SKG小鼠一样，会产生类风湿因子抗体，但不会产生自身免疫性关节炎。由ZAP-70突变引起的信号差异似乎以不同的方式扭曲了TCR库，从而影响自身免疫倾向与自身免疫性疾病易感性。在胸腺选择过程中，通过分离T调节细胞和TCR库的相对贡献，我们的数据有助于确定对自身免疫性疾病的发展可能重要但单独不够的事件。
ZAP-70 is critical for T cell receptor (TCR) signaling. Tyrosine to phenylalanine mutations of Y315 and Y319 in ZAP-70 suggest these residues function to recruit downstream effector molecules, but mutagenesis and crystallization studies reveal that these residues also play an important role in autoinhibition ZAP-70. To address the importance of the scaffolding function, we generated a zap70 mutant mouse (YYAA mouse) with Y315 and Y319 both mutated to alanines. These YYAA mice reveal that the scaffolding function is important for normal development and function. Moreover, the YYAA mice have many similarities to a previously identified ZAP-70 mutant mouse, SKG, which harbors a distinct hypomorphic mutation. Both YYAA and SKG mice have impaired T cell development and hyporesponsiveness to TCR stimulation, markedly reduced numbers of thymic T regulatory cells and defective positive and negative selection. YYAA mice, like SKG mice, develop rheumatoid factor antibodies, but fail to develop autoimmune arthritis. Signaling differences that result from ZAP-70 mutations appear to skew the TCR repertoire in ways that differentially influence propensity to autoimmunity versus autoimmune disease susceptibility. By uncoupling the relative contribution from T regulatory cells and TCR repertoire during thymic selection, our data help to identify events that may be important, but alone are insufficient, for the development of autoimmune disease.
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影响因子：
64.5
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
32.4
作者：
Siggs, Owen M.;Miosge, Lisa A.;Goodnow, Christopher C.
通讯作者：
Goodnow, Christopher C.
影响因子：
4.8
作者：
Gelkop, S;Isakov, N
通讯作者：
Isakov, N
影响因子：
64.8
作者：
Sakaguchi, N;Takahashi, T;Sakaguchi, S
通讯作者：
Sakaguchi, S
DOI：
10.1073/pnas.94.26.14602
发表时间：
1997-12-23
影响因子：
11.1
作者：
O'Gorman, S;Dagenais, NA;Marchuk, Y
通讯作者：
Marchuk, Y