Delineation of antigen-specific and antigen-nonspecific CD8+ memory T-cell responses after cytokine-based cancer immunotherapy
Delineation of antigen-specific and antigen-nonspecific CD8+ memory T-cell responses after cytokine-based cancer immunotherapy
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DOI：
10.1182/blood-2011-07-369736
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发表时间：
2012-03-29
期刊：
影响因子：
20.3
通讯作者：
Murphy, William J.
中科院分区：
文献类型：
--
作者：
Tietze, Julia K.;Wilkins, Danice E. C.;Murphy, William J.
记忆T细胞在免疫系统中表现出巨大的抗原特异性，并随着年龄的增长而积累。我们的研究揭示了记忆性CD 8（+）T细胞的抗原非依赖性扩增，但在几种针对癌症的免疫治疗方案后，幼稚CD 8（+）T细胞的扩增不依赖于抗原，从而导致独特的表型。通过小鼠和人类记忆CD 8（+）T细胞中的T细胞受体（TCR）或CD 3的信号传导显著上调程序性死亡-1（PD-1）和CD 25（IL-2受体α链），并导致抗原特异性肿瘤细胞杀伤。相比之下，在体外单独暴露于细胞因子或在体内暴露于免疫疗法并不上调这些标志物，但导致扩增的记忆性CD 8（+）T细胞表达NKG 2D、颗粒酶B，并具有广泛的裂解能力。在小鼠中阻断NKG 2D也导致免疫治疗后抗肿瘤作用显著减弱。用免疫疗法治疗携带非抗原表达肿瘤的TCR转基因小鼠仍然产生显著的抗肿瘤作用。从局部应用免疫调节剂治疗后的患者中获得的人类黑素瘤组织活检导致肿瘤部位内这些CD 8（+）CD 25（-）细胞的数量增加。这些发现表明，记忆性CD 8（+）T细胞可以表达差异表型指示适应性或先天性效应器的基础上的性质的刺激在整个物种保守的过程。（血。2012;119（13）：3073-3083）
Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8(+) T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor alpha chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8(+) T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8(+) CD25(-) cells within the tumor site. These findings demonstrate that memory CD8(+) T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species. (Blood. 2012;119(13):3073-3083)