Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy.
Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy.
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DOI：
10.1186/s40425-017-0235-4
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发表时间：
2017
影响因子：
10.9
通讯作者：
Murphy WJ
中科院分区：
文献类型：
--
作者：
Sckisel GD;Mirsoian A;Minnar CM;Crittenden M;Curti B;Chen JQ;Blazar BR;Borowsky AD;Monjazeb AM;Murphy WJ
评估免疫参数的研究通常利用人的PBMCs或小鼠的脾细胞来产生被解释为代表免疫状态的数据。使用脾细胞，我们发现在全身免疫刺激治疗后扩张的记忆CD4-T细胞经历了IFNG介导的快速激活诱导细胞死亡(AICD)，导致与PD-1表达升高相关的总CD4-T细胞的净损失。这与CD8-T细胞不同，CD8-T细胞在最小的PD-1上调和凋亡的情况下扩张。在这项研究中，我们通过评估CD4和CD8-T细胞在外周器官中的表型和分布来扩展我们以前的工作，这两种细胞更能代表免疫治疗后转移部位发生的免疫反应。对对照组和免疫治疗组小鼠的淋巴器官(脾和层粘连)以及外周器官(肝和肺)中的T细胞进行表型分析，以观察不同位置对记忆表型和激活标记状态的影响。同时检测接受全身大剂量IL-2治疗的患者外周血中PD-1的表达和记忆表型。在这里，我们发现，与在脾和淋巴结中发生的情况类似，在这些外围部位，CD4-T细胞数量减少，而CD8-T细胞数量增加。与在脾中出现的PD-1的差异表达相反，CD4和CD8-T细胞在肝脏和肺中的PD-1水平都显著升高。进一步分析PD-1的表达与CD62Llow(T效应器/效应器记忆，TE/EM)的表达之间的关系，CD62Llow在外周器官的CD8-T细胞和CD4-T细胞中普遍存在。在接受全身大剂量IL-2治疗的患者中，TE/EM细胞上PD-1的表达也有类似的升高。这些数据强调了循环中T细胞的PD-1表达和/或TE/EM亚群更能代表免疫部位的细胞，并强调了在确定免疫状态时对淋巴和靶器官进行评估的重要性。临床试验.gov NCT01416831。注册日期为2011年8月12日。本文的在线版本(doi：10.1186/s40425-0170235-4)包含补充材料，授权用户可以使用。
Studies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis. In this study we expand upon our previous work by evaluating CD4 and CD8-T cell phenotype and distribution in peripheral organs which are more representative of immune responses occurring at metastatic sites following immunotherapy. Phenotypic assessment of T cells in both lymphoid (spleen and LN) as well as peripheral organs (liver and lungs) in control and immunotherapy treated mice was performed to survey the impact of location on memory phenotype and activation marker status. Peripheral blood from patients undergoing systemic high dose IL-2 was also assessed for expression of PD-1 and memory phenotype. Here we reveal that, similar to what occurs in the spleen and lymph nodes, CD4-T cell numbers decreased while CD8-T cells expanded at these peripheral sites. In contrast to having differential expression of PD-1 as occurs in the spleen, both CD4 and CD8-T cells had significantly elevated levels of PD-1 in both the liver and lungs. Further analysis correlated PD-1 expression to CD62Llow (T effector/effector memory,TE/EM) expression which are more prevalent in CD4-T cells in general as well as CD8-T cells in peripheral organs. Similar elevated PD-1 expression on TE/EM cells was observed in patients undergoing systemic high-dose IL-2 therapy. These data highlight PD-1 expressing and/or TE/EM subsets of T cells in circulation as more representative of cells at immune sites and underscore the importance of valuation both in lymphoid as well as target organs when making determinations about immune status. ClinicalTrials.gov NCT01416831. Registered August 12, 2011. The online version of this article (doi:10.1186/s40425-017-0235-4) contains supplementary material, which is available to authorized users.