Hughes D P M, Baskar D, Urban F F, Friedman M S, Braun T M, McDonagh K T
Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cytotherapy. 2005;7(5):396-407. doi: 10.1080/14653240500319127.
Adoptive immunotherapy with T cells activated through CD3 alone requires exogenous IL-2 for T-cell function and survival after transfer, but the in vivo cytokine requirement of T cells activated through CD3 and CD28 is unknown. We hypothesized that CD3/CD28-activated T cells, unlike those activated through CD3 alone, might develop into long-lived memory T cells, either with or without systemic IL-2.
We used MHC class I-restricted TCR transgenic T cells from the OT-1 mouse, specific for the surrogate tumor Ag ovalbumin (OVA), to assess the trafficking kinetics, antigenic responsiveness and anti-tumor efficacy of dual-activated T cells in vivo as a function of IL-2 administration. At days 7, 14, and 28 after transfer, lymph node cells and splenocytes were examined for donor cell persistence and antigenic responsiveness by FACS and ELISA, respectively.
In IL-2-treated mice, donor CD8+ T cells persisted and developed a memory phenotype, based on CD44 and Ly6c expression at day 28, while mice given no IL-2 had fewer donor cells at all time points. OVA-specific release of IFN-gamma was higher from lymphocytes of IL-2-treated mice compared with no-IL-2 mice (P<0.02 at all time points). In mice challenged with an OVA-bearing subline of the AML leukemia model C1498, IL-2 did not confer added protection from tumor challenge at 1 or 2 weeks after adoptive transfer, but gave improved survival at 4 weeks post-transfer.
We conclude that exogenous IL-2 is not required for anti-tumor activity of CD3/CD28-activated CD8+ cells early after adoptive transfer, but promotes T-cell persistence that confers disease protection at more remote times.
单纯通过CD3激活的T细胞进行过继性免疫治疗，在转移后T细胞功能及存活需要外源性白细胞介素-2（IL-2），但通过CD3和CD28激活的T细胞在体内对细胞因子的需求尚不清楚。我们推测，与单纯通过CD3激活的T细胞不同，通过CD3/CD28激活的T细胞无论有无全身性IL-2，都可能发育为长寿记忆T细胞。
我们使用来自OT-1小鼠的MHC I类限制性TCR转基因T细胞，其对替代肿瘤抗原卵清蛋白（OVA）具有特异性，以评估双重激活的T细胞在体内的迁移动力学、抗原反应性和抗肿瘤功效与IL-2给药的关系。在转移后第7、14和28天，分别通过流式细胞术（FACS）和酶联免疫吸附测定（ELISA）检测淋巴结细胞和脾细胞中供体细胞的持久性和抗原反应性。
在接受IL-2治疗的小鼠中，供体CD8+T细胞持续存在，并在第28天根据CD44和Ly6c表达呈现记忆表型，而未接受IL-2治疗的小鼠在所有时间点的供体细胞均较少。与未接受IL-2治疗的小鼠相比，接受IL-2治疗的小鼠淋巴细胞释放的OVA特异性γ干扰素更高（所有时间点P<0.02）。在用AML白血病模型C1498的OVA携带亚系攻击的小鼠中，IL-2在过继转移后1或2周时并未提供额外的肿瘤攻击保护，但在转移后4周时提高了存活率。
我们得出结论，过继转移后早期，CD3/CD28激活的CD8+细胞的抗肿瘤活性不需要外源性IL-2，但可促进T细胞持久性，从而在更晚的时候提供疾病保护。
