Pre-TCR ligand binding impacts thymocyte development before αβTCR expression
Pre-TCR ligand binding impacts thymocyte development before αβTCR expression
复制标题
DOI：
10.1073/pnas.1504971112
复制
发表时间：
2015-07-07
影响因子：
11.1
通讯作者：
Reinherz, Ellis L.
中科院分区：
文献类型：
--
作者：
Mallis, Robert J.;Bai, Ke;Reinherz, Ellis L.
适应性细胞免疫需要精确的自我vs。非自我歧视，以防止感染和肿瘤转化，同时排除自身免疫。这种至关重要的能力是通过选择识别与MHC分子结合的肽的α β t细胞受体（α β TCRs）在胸腺中编程的。在这里，我们发现pre-TCR (precr)，一种出现在α - β TCR表达之前的pT α - β异二聚体，指导了先前未被发现的曲目选择的初始阶段。与precr功能的配体无关模型相比，我们通过核磁共振和生物力探针分析发现，β亚基结合pMHC使用V β互补决定区域以及precr暴露的疏水V β斑块特征。力调节单键类似于α - β TCRs，但具有更混杂的配体特异性，可触发钙通量。因此，胸腺发育涉及连续的β -和α - β -曲目调整，通过precr与自身pMHC的相互作用调节早期胸腺细胞扩增，这意味着β -选择、免疫优势肽识别和种系编码的MHC相互作用。
Adaptive cellular immunity requires accurate self-vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of alpha beta T-cell receptors (alpha beta TCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pT alpha-beta heterodimer appearing before alpha beta TCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligand-independent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the beta-subunit binds pMHC using V beta complementarity-determining regions as well as an exposed hydrophobic V beta patch characteristic of the preTCR. Force-regulated single bonds akin to those of alpha beta TCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential beta- and then, alpha beta-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for beta-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction.