Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions.
Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions.
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DOI：
10.1371/journal.pone.0085882
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Stepkowski SM
中科院分区：
文献类型：
--
作者：
Khattar M;Miyahara Y;Schroder PM;Xie A;Chen W;Stepkowski SM
最佳的T细胞活化和扩增需要共同的γ-链（γc）细胞因子白细胞介素-2（IL-2）与其同源受体结合，后者进而参与γc/Janus酪氨酸激酶（Jak）3信号传导途径。由于其受抗原活化的T细胞的限制性表达及其在促进其存活和增殖中的强制性作用，IL-2已被认为是预防T细胞介导的疾病的选择性治疗靶点。然而，为了进一步探索IL-2靶向治疗，准确了解其在T细胞活化早期事件中的作用至关重要。在这项研究中，我们描绘了IL-2和其他γc细胞因子在促进CD 4和CD 8 T细胞在早期阶段的启动存活的作用。在IL-2抑制条件下（通过中和抗IL-2 mAb），活化的CD 8 + T细胞的存活率降低，而CD 4 + T细胞保持更高的抗性。与CD 4 + T细胞相比，这些结果与CD 8 + T细胞中Bcl-2表达和线粒体膜电位降低相关。然而，使用transwell共培养测定，我们已经发现，即使在IL-2缺乏的条件下，CD 4 + T细胞也可以通过分泌可溶性因子来拯救CD 8 + T细胞的存活。对单独培养的CD 8 + T细胞进行的细胞因子筛选显示，IL-21（另一种γc细胞因子）能够挽救它们在IL-2剥夺下的存活。事实上，阻断IL-21信号传导途径沿着IL-2中和导致CD 4+和CD 8 + T细胞的存活率显著降低。总之，我们已经表明，在IL-2剥夺条件下，IL-21可能作为促进T细胞免疫应答的主要存活因子。因此，IL-2靶向治疗的研究可能需要重新审视，以考虑将IL-21信号通路的阻断作为辅助手段，以提供更有效的T细胞免疫应答控制。
Optimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory role in promoting their survival and proliferation, IL-2 has been considered as a selective therapeutic target for preventing T cell mediated diseases. However, in order to further explore IL-2 targeted therapy, it is critical to precisely understand its role during early events of T cell activation. In this study, we delineate the role of IL-2 and other γc cytokines in promoting the survival of CD4 and CD8 T cells during early phases of priming. Under IL-2 inhibitory conditions (by neutralizing anti-IL-2 mAbs), the survival of activated CD8+ T cells was reduced, whereas CD4+ T cells remained much more resistant. These results correlated with reduced Bcl-2 expression, and mitochondrial membrane potential in CD8+ T cells in comparison to CD4+ T cells. However, using transwell co-culture assays we have found that CD4+ T cells could rescue the survival of CD8+ T cells even under IL-2 deprived conditions via secretion of soluble factors. A cytokine screen performed on CD8+ T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation. Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4+ and CD8+ T cells. Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses. Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses.
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