Tuning T cell activation threshold and effector function with cross-reactive peptide ligands
Tuning T cell activation threshold and effector function with cross-reactive peptide ligands
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DOI：
10.1093/intimm/12.2.205
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发表时间：
2000-02-01
影响因子：
4.4
通讯作者：
Kuchroo, VK
中科院分区：
文献类型：
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作者：
Nicholson, LB;Anderson, AC;Kuchroo, VK
我们通过用Q144肽免疫SJL小鼠（I-A（S））产生了一组交叉反应性T细胞，Q144肽是髓鞘蛋白脂质蛋白（PLP）139-151的自身抗原肽（W144）的类似物在用Q144免疫后，用W144体外扩增T细胞，W144是交叉反应性的，次优配体，用于Q144特异性T细胞。T细胞克隆对两种配体都有反应，并在肽W144上正常生长，但在体外被Q144激活时过度刺激。这种过度刺激导致异型增殖反应，分泌非由W144诱导的额外细胞因子。因此，通过次优交叉反应性配体的T细胞扩增有效地降低了活化阈值，使得免疫抗原成为克隆的过度刺激配体。令人惊讶的是，当T细胞克隆在超刺激配体Q144上生长时，一些通过增加其激活阈值来适应。这种脱敏导致对许多交叉反应性配体的反应丧失，并出现更特异性的T细胞反应。与超刺激配体的长期培养有时与CD 4表达的下调有关。这些结果为T细胞异嗜性的常见发现提供了解释，并表明尽管T细胞对肽的反应的特异性和层次由TCR决定，但活化阈值和效应器功能通过暴露于交叉反应性配体而改变，该观察结果对自身免疫性疾病的发展和调节具有意义。
We have generated a panel of cross-reactive T cells by immunizing SJL mice (I-A(S)) with Q144 peptide, an analog of an autoantigenic peptide (W144) of myelin proteolipid protein (PLP) 139-151 (HSLGKWLGHPDKF) in which W was replaced by Q at position 144, Following immunization with Q144, T cells were expanded in vitro with W144, which is a cross-reactive, suboptimal ligand, for Q144-specific T cells. The T cell clones responded to both ligands and grew normally on the peptide W144, but were hyperstimulated when activated by Q144 in vitro. This hyperstimulation results in a heteroclitic proliferative response with secretion of additional cytokines not induced by W144, Thus expansion of T cells by a suboptimal cross-reactive ligand effectively lowers the activation threshold so that the immunizing antigen becomes a hyperstimulating ligand for the clones. Surprisingly, when the T cell clones are grown on the hyperstimulating ligand Q144, some adapt by increasing their activation threshold. This desensitization results in a loss of response to a number of cross-reactive ligands and the appearance of a more specific T cell response. Longterm culture with the hyperstimulating ligand is sometimes associated with down-regulation of CD4 expression. These results provide an explanation for the common finding of T cell heteroclicity, and suggest that although the specificity and hierarchy of the response of T cells to peptides is determined by the TCR, activation threshold and effector functions are modified by exposure to cross-reactive ligands, This observation has implications for the development and regulation of autoimmune disease.