Costimulatory strength influences the differential effects of transforming growth factor β1 for the generation of CD8+ regulatory T cells
Costimulatory strength influences the differential effects of transforming growth factor β1 for the generation of CD8+ regulatory T cells
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DOI：
10.1016/j.molimm.2008.01.019
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Roy, Edward J.
中科院分区：
文献类型：
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作者：
Fan, Timothy M.;Kranz, David M.;Roy, Edward J.
转化生长因子 β 1 (TGF β 1) 是一种多效细胞因子，能够发挥多种生物效应。尽管它在多种免疫活动中发挥着核心作用，但负责塑造 TGF beta 1 免疫特性的分子信号仍不清楚。我们报道共刺激强度充当分子开关，影响TGFβ1对初始CD8(+)淋巴细胞的效应器和调节发育的差异作用。在低共刺激下，TGFβ1抑制CD8(+)淋巴细胞的增殖和细胞因子分泌，但在高共刺激下，对TGFβ1的反应有很大不同。高共刺激与TGFβ1结合产生CD8(+)CD25(+)T淋巴细胞，其在低IL-2浓度存在下保持强大的增殖和存活能力。此外，在这些条件下，产生了表达Foxp3、分泌IL-10并通过接触依赖性机制抑制幼稚T淋巴细胞增殖的CD8(+)T淋巴细胞亚群。将这些 CD8(+)CD25(+)Foxp3(+) T 细胞过继转移到静脉内接种 B16F10 黑色素瘤的小鼠体内似乎会加速肿瘤进展，这反映在肺转移性肿瘤灶数量的增加。这些发现表明，共刺激强度可能充当CD8+T细胞生成的分子开关，CD8+T细胞具有调节表型并能够减少荷瘤小鼠体内的抗肿瘤免疫反应。 (c) 2008 Elsevier Ltd. 保留所有权利。
Transforming growth factor beta 1 (TGF beta 1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGF beta 1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGF beta 1 on the effector and regulatory development of naive CD8(+) lymphocytes. At low costimulation, TGF beta 1 inhibits proliferation of CD8(+) lymphocytes and cytokine secretion, but at high costimulation the response to TGF beta 1 is quite different. High costimulation combined with TGF beta 1 generates CD8(+)CD25(+) T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8(+) T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit naive T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8(+)CD25(+)Foxp3(+) T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8(+) T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice. (c) 2008 Elsevier Ltd. All rights reserved.