The half-life of the T-cell receptor/peptide-major histocompatibility complex interaction can modulate T-cell activation in response to bacterial challenge
The half-life of the T-cell receptor/peptide-major histocompatibility complex interaction can modulate T-cell activation in response to bacterial challenge
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DOI：
10.1111/j.1365-2567.2007.02561.x
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发表时间：
2007-06-01
期刊：
影响因子：
6.4
通讯作者：
Kalergis, Alexis M.
中科院分区：
文献类型：
--
作者：
Carreno, Leandro J.;Bueno, Susan M.;Kalergis, Alexis M.
T 细胞激活是由于抗原呈递细胞 (APC) 表面的同源肽-主要组织相容性复合物 (pMHC) 复合物与 T 细胞受体 (TCR) 的结合所致。先前的研究提供了支持 TCR/pMHC 相互作用的半衰期和 APC 上 pMHC 密度是影响 T 细胞激活的两个参数这一观点的证据。然而，TCR/pMHC 相互作用的半衰期是否可以调节 T 细胞激活以应对病原体挑战仍然未知。为了解决这个问题，我们培育了表达卵清蛋白 (OVA) 抗原变体的细菌菌株，这些变体在 SIINFEKL 序列中携带点突变。当与 H-2K(b) 结合时，该肽是 OT-I TCR 的同源配体。 H-2K(b)/SIINFEKL 的变体以不同的半衰期与 OT-I TCR 结合。在这里，我们发现，当 TCR/H-2K(b)/OVA 相互作用的半衰期过短时，感染表达 OVA 变体的细菌的树突状细胞 (DC) 无法激活 OT-I T 细胞。与这些数据一致的是，仅在感染表达 OVA 变体的细菌的小鼠中观察到 T 细胞激活，这些 OVA 变体与 OT-I 结合，半衰期超过一定阈值。综合考虑，我们的数据表明 TCR/pMHC 相互作用的半衰期可以显着调节体内 T 细胞活化，并影响细菌表达的抗原的识别。这些观察结果强调了 TCR/pMHC 半衰期对病原体清除的重要性。
T-cell activation results from engagement of the T-cell receptor (TCR) by cognate peptide-major histocompatibility complex (pMHC) complexes on the surface of antigen-presenting cells (APC). Previous studies have provided evidence supporting the notion that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters that can influence T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate T-cell activation in response to a pathogen challenge remains unknown. To approach this question, we generated strains of bacteria expressing variants of the ovalbumin (OVA) antigen, carrying point mutations in the SIINFEKL sequence. When bound to H-2K(b), this peptide is the cognate ligand for the OT-I TCR. Variants of the H-2K(b)/SIINFEKL bind to the OT-I TCR with distinct half-lives. Here we show that dendritic cells (DCs) infected with bacteria expressing OVA variants were incapable of activating OT-I T cells when the half-life of the TCR/H-2K(b)/OVA interaction was excessively short. Consistent with these data, T-cell activation was only observed in mice infected with bacteria expressing OVA variants that bound to OT-I with a half-life above a certain threshold. Considered together, our data suggest that the half-life of TCR/pMHC interaction can significantly modulate T-cell activation in vivo, as well as influence recognition of antigens expressed by bacteria. These observations underscore the importance of the TCR/pMHC half-life on the clearance of pathogens.