The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla.
The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla.
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DOI：
10.4049/jimmunol.0901104
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Laufer TM
中科院分区：
文献类型：
--
作者：
Stephen TL;Tikhonova A;Riberdy JM;Laufer TM
未成熟的胸腺细胞是根据其对自体多肽-MHC复合体的反应而被积极选择的，它们会发育成成熟的T细胞，对相同的复合体没有明显的反应。发育调节是一个活跃的过程，通过这个过程，单个阳性胸腺细胞的TCR相关信号通路被减弱，以对外围将遇到的多肽-MHC分子做出适当的反应。在这项研究中，我们探索了在胸腺髓质中遇到的调节CD4+单阳性T细胞向MHC II类调节的机制。用小鼠骨髓嵌合体进行的实验表明，胸腺髓质上皮细胞或胸腺树突状细胞表达的MHC II类分子可以介导这种调节。调谐不需要MHC II类细胞与基质细胞接触。相反，它是通过MHC II类分子和TCR之间的相互作用来调节的。为了了解未成熟的高活性T细胞与经过调节的成熟的CD4+T细胞的分子变化，我们比较了它们对TCR刺激的反应。成熟的CD4单阳性胸腺细胞的改变反应的特征是低亲和力的自我配体抑制ERK的激活，以及抑制酪氨酸磷酸酶SHP-1的表达增加。因此，胸腺髓质基质上多肽-MHC-II类持续的TCR结合抑制了对自身AGS的反应性，并阻止了成熟谱系中的自身反应性。
Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4+ single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4+T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
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影响因子：
32.4
作者：
Ernst, B;Lee, DS;Surh, CD
通讯作者：
Surh, CD
影响因子：
56.9
作者：
GRUSBY, MJ;JOHNSON, RS;GLIMCHER, LH
通讯作者：
GLIMCHER, LH
影响因子：
56.9
作者：
FungLeung, WP;Surh, CD;Karlsson, L
通讯作者：
Karlsson, L
DOI：
10.1073/pnas.84.12.4205
发表时间：
1987-06-01
影响因子：
11.1
作者：
COSULICH, ME;RUBARTELLI, A;BARGELLESI, A
通讯作者：
BARGELLESI, A
影响因子：
4.4
作者：
Gil, Diana;Schrum, Adam G.;Palmer, Ed
通讯作者：
Palmer, Ed