Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains.
Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains.
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作者：
将外源性T细胞受体（TCR）基因导入患者活化的外周血T细胞是产生大量用于过继治疗癌症和病毒性疾病的特异性T细胞的有效策略。然而，这种强大方法的显著临床前景仍然被严重的潜在后果所掩盖：外源性TCR链与内源性TCR链的错配。这些“混合”异二聚体可以产生新的特异性，导致移植物抗宿主反应。用半胱氨酸改造外源链的TCR恒定区可促进正确配对并减少错配，但如我们在此所示，不能消除混合异源二聚体的形成。相比之下，通过使用稳定的Vα/Vβ单链TCR（scTv）来删除恒定区，完全避免了错配。通过将高亲和力scTv连接至细胞内信号传导结构域，如Lck和CD 28，scTv能够在不存在CD 3亚基或共受体的情况下激活功能性T细胞应答，并避免与内源性TCR的错配。这种转导的T细胞可以通过引入的scTv独立于CD 3亚基对靶向抗原产生应答，而转导的T细胞不会获得任何新的不确定的和潜在危险的特异性。
Transduction of exogenous T cell receptor (TCR) genes into patients’ activated peripheral blood T cells is a potent strategy to generate large numbers of specific T cells for adoptive therapy of cancer and viral diseases. However, the remarkable clinical promise of this powerful approach is still being overshadowed by a serious potential consequence: mispairing of the exogenous TCR chains with endogenous TCR chains. These “mixed” heterodimers can generate new specificities that result in graft-versus-host reactions. Engineering TCR constant regions of the exogenous chains with a cysteine promotes proper pairing and reduces the mispairing, but, as we show here, does not eliminate the formation of mixed heterodimers. By contrast, deletion of the constant regions, through use of a stabilized Vα/Vβ single-chain TCR (scTv), avoided mispairing completely. By linking a high-affinity scTv to intracellular signaling domains, such as Lck and CD28, the scTv was capable of activating functional T cell responses in the absence of either the CD3 subunits or the co-receptors, and circumvented mispairing with endogenous TCRs. Such transduced T cells can respond to the targeted antigen independent of CD3 subunits via the introduced scTv, without the transduced T cells acquiring any new undefined and potentially dangerous specificities.
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DOI：
10.1084/jem.191.2.335
发表时间：
2000-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Daniels MA;Jameson SC
通讯作者：
Jameson SC
影响因子：
12.4
作者：
Dossett, Michelle L.;Teague, Ryan M.;Schmitt, Thomas M.;Tan, Xiaoxia;Cooper, Laurence J. N.;Pinzon, Cristina;Greenberg, Philip D.
通讯作者：
Greenberg, Philip D.
DOI：
10.1093/protein/gzg087
发表时间：
2003-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Boulter, JM;Glick, M;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
3.6
作者：
Bartok, Istvan;Holland, Stephen J.;Dyson, Julian
通讯作者：
Dyson, Julian
影响因子：
20.3
作者：
Heemskerk, Mirjam H. M.;Hagedoorn, Renate S.;Falkenburg, J. H. Frederik
通讯作者：
Falkenburg, J. H. Frederik