Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8+ T-cell proliferation by distinct pathways
Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8+ T-cell proliferation by distinct pathways
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DOI：
10.1002/eji.201445312
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发表时间：
2015-05-01
影响因子：
5.4
通讯作者：
Akbar, Arne N.
中科院分区：
文献类型：
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作者：
Henson, Sian M.;Macaulay, Richard;Akbar, Arne N.
在免疫力降低导致发病率增加的情况下，免疫增强是理想的。我们研究了阻断表面抑制性受体PD-1和/或p38 MAP激酶是否可以增强效应记忆CD 8（+）T细胞亚群的增殖，该亚群重新表达CD 45 RA（EMRA）并表现出衰老特征，包括增殖和端粒酶活性降低，但DNA损伤反应相关蛋白H2 AX表达增加。阻断这些细胞中的PD-1和p38 MAPK信号传导增强了增殖，并且当在年轻和老年人受试者中同时抑制两种途径时，这种增加是累加的。相比之下，EMRA CD 8（+）T细胞中的端粒酶活性仅通过阻断p38而不是PD-1信号通路来增强，进一步表明涉及非重叠信号通路。虽然阻断p38 MAPK抑制EMRA群体中的TNF-α分泌，但这种减少被这些细胞中PD-1信号传导的同时抑制所抵消。因此，EMRA CD 8（+）T细胞的终末期特征受到不同且可逆的细胞信号传导事件的严格控制。此外，PD-1和p38信号传导通路的抑制一起可以增强EMRA CD 8（+）T细胞的增殖，而不会损害其细胞因子分泌的能力。
Immune enhancement is desirable in situations where decreased immunity results in increased morbidity. We investigated whether blocking the surface inhibitory receptor PD-1 and/or p38 MAP kinase could enhance the proliferation of the effector memory CD8(+) T-cell subset that re-expresses CD45RA (EMRA) and exhibits characteristics of senescence, which include decreased proliferation and telomerase activity but increased expression of the DNA damage response related protein H2AX. Blocking of both PD-1 and p38 MAPK signaling in these cells enhanced proliferation and the increase was additive when both pathways were inhibited simultaneously in both young and old human subjects. In contrast, telomerase activity in EMRA CD8(+) T cells was only enhanced by blocking the p38 but not the PD-1 signaling pathway, further indicating that nonoverlapping signaling pathways were involved. Although blocking p38 MAPK inhibits TNF- secretion in the EMRA population, this decrease was counteracted by the simultaneous inhibition of PD-1 signaling in these cells. Therefore, end-stage characteristics of EMRA CD8(+) T cells are stringently controlled by distinct and reversible cell signaling events. In addition, the inhibition of PD-1 and p38 signaling pathways together may enable the enhancement of proliferation of EMRA CD8(+) T cells without compromising their capacity for cytokine secretion.