Quantitative phosphoproteomic analysis of T cell receptor signaling in diabetes prone and resistant mice.
Quantitative phosphoproteomic analysis of T cell receptor signaling in diabetes prone and resistant mice.
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DOI：
10.1021/pr100035b
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发表时间：
2010-06-04
影响因子：
4.4
通讯作者：
White FM
中科院分区：
文献类型：
--
作者：
Iwai LK;Benoist C;Mathis D;White FM
人类患者和NOD小鼠的1型糖尿病是由自身反应性T淋巴细胞对胰腺产生胰岛素的β细胞的免疫攻击引起的。在NOD小鼠中，抗原特异性T细胞受体（TCR）下游信号传导途径的遗传控制扰动可能有助于T细胞反应的改变，表现为胸腺中识别自身抗原后细胞凋亡的诱导效率低下，或外周器官中成熟T细胞的反应性受到干扰。为了绘制这种信号差异，我们使用基于质谱的定量磷酸蛋白质组学来比较糖尿病易感NOD和耐药B6.H2g7小鼠的原代CD 4 + T细胞的活化。酪氨酸磷酸化肽的免疫沉淀和IMAC纯化，结合稳定同位素iTRAQ标记，使我们能够鉴定和定量原代CD 4 + T细胞TCR刺激下游54种不同蛋白质中超过77个磷酸化事件。该分析显示，在活化的NOD细胞中磷酸酪氨酸水平普遍较高，以及在这两种菌株中似乎受到差异调节的几个磷酸化位点（涉及TXK、CD 5、PAG 1和ZAP-70）。这些数据突出了NOD和B6 g7小鼠的CD 4 + T细胞区室之间的信号传导差异，并且可能是NOD小鼠中T细胞失调的基础。
Type 1 diabetes, in human patients and NOD mice, results from immune attack on insulin-producing beta-cells of the pancreas by autoreactive T lymphocytes. In NOD mice, genetically-controlled perturbations in the signaling pathways downstream of the antigen-specific T cell receptor (TCR) may be instrumental in the altered responses of T cells, manifest as inefficient induction of apoptosis after recognition of self-antigens in the thymus, or as perturbed reactivity of mature T cells in peripheral organs. To map this signaling difference(s), we have used mass spectrometry-based quantitative phosphoproteomics to compare the activation of primary CD4+ T cells of diabetes-prone NOD and -resistant B6.H2g7 mice. Immunoprecipitation and IMAC purification of tyrosine-phosphorylated peptides, combined with a stable-isotope iTRAQ labeling, enabled us to identify and quantify over 77 phosphorylation events in 54 different proteins downstream of TCR stimulation of primary CD4+ T cells. This analysis showed a generally higher level of phosphotyrosine in activated NOD cells, as well as several phosphorylation sites that appeared to be differentially regulated in these two strains (involving TXK, CD5, PAG1, and ZAP-70). These data highlight the differences in signaling between CD4+ T cell compartments of NOD and B6g7 mice, and may underlie the dysregulation of T cells in NOD mice.
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影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
4.8
作者：
Mege, D;DiBartolo, V;Acuto, O
通讯作者：
Acuto, O
影响因子：
15.3
作者：
Lesage, S;Hartley, SB;Goodnow, CC
通讯作者：
Goodnow, CC
DOI：
10.1073/pnas.0708899104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Feuerer, Markus;Jiang, Wenyu;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
30.5
作者：
Kishimoto, H;Sprent, J
通讯作者：
Sprent, J