Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression.
Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression.
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DOI：
10.1007/s00262-011-1043-1
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Guevara-Patiño JA
中科院分区：
文献类型：
--
作者：
O'Sullivan JA;Zloza A;Kohlhapp FJ;Moore TV;Lacek AT;Dulin NO;Guevara-Patiño JA
虽然已经分别研究了 TCR 亲和力和 TGFβ 对 CD8+ T 细胞功能的影响，但 TCR 亲和力决定对 TGFβ 介导的抑制的易感性的方式仍然未知。为了解决这个问题，我们在 OT-I 模型中利用了不同亲和力的 OVA 改变的肽配体 (APL)。我们证明，虽然降低的 TCR 配体亲和力最初会导致反应减弱，但这种相互作用会促使效应细胞在二次暴露时对同源抗原做出更强烈的反应。尽管如此，用低亲和力 TCR 配体引发的 CD8+ T 细胞的反应可以更有效地受到 TGFβ 的调节。对 TGFβ 介导的抑制的敏感性与 RGS3 的下调有关，RGS3 是最近公认的 TGFβ 信号传导的负调节因子，但与 TGFβ 受体 I/II 的表达无关。这些结果表明了一种新的耐受机制，其中 CD8+ T 细胞根据它们最初引发的配体的亲和力受到 TGFβ 的有区别的调节。此外，由于 TGFβ 在肿瘤诱导的免疫抑制中发挥着重要作用，这些结果表明引发配体的亲和力是 CD8+ T 细胞介导的癌症免疫治疗策略中的主要关注点。
While the effects of TCR affinity and TGFβ on CD8+ T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFβ-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8+ T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFβ. Susceptibility to TGFβ-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFβ signaling, but not expression of TGFβ receptors I/II. These results suggest a novel tolerance mechanism whereby CD8+ T cells are discriminately regulated by TGFβ according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFβ in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8+ T-cell-mediated cancer immunotherapeutic strategies.
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影响因子：
15.3
作者：
Fahlén, L;Read, S;Gorelik, L;Hurst, SD;Coffman, RL;Flavell, RA;Powrie, F
通讯作者：
Powrie, F
影响因子：
32.4
作者：
Marie, Julien C.;Liggitt, Denny;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
32.4
作者：
Sanjabi, Shomyseh;Mosaheb, Munir M.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
3
作者：
Desser, L;Holomanova, D;Herbacek, I
通讯作者：
Herbacek, I