High avidity cytotoxic T lymphocytes can be selected into the memory pool but they are exquisitely sensitive to functional impairment.
High avidity cytotoxic T lymphocytes can be selected into the memory pool but they are exquisitely sensitive to functional impairment.
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DOI：
10.1371/journal.pone.0041112
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Durrant LG
中科院分区：
文献类型：
--
作者：
Brentville VA;Metheringham RL;Gunn B;Durrant LG
高亲和力细胞毒性T淋巴细胞（CTL）在病毒清除和抗肿瘤免疫中具有重要作用，然而，其在体内最佳产生和维持的机制仍不清楚。用编码单个CTL表位的抗体-DNA疫苗免疫小鼠，诱导比用相同表位的肽疫苗高100倍的亲合力应答。高亲合力反应被保留在记忆中，并且可以用抗体-DNA加强有效地重新激活。相比之下，用肽再活化高亲合力CTL，刺激亲合力显著下降的应答，表明高亲合力CTL丧失或转化为较低亲合力。类似地，离体维持的高亲合力T细胞对低剂量肽（1 ng/ml）的信号传导非常敏感，从而产生最佳TCR刺激并导致保留的亲合力、增殖和杀死特异性靶标的能力。相比之下，用超最佳TCR刺激（10 μg/ml肽）离体维持的高亲合力T细胞导致亲合力降低且不能杀死肿瘤细胞。它们也未能增殖，细胞凋亡显著增加，并表达高水平的耗竭标记物程序性死亡-1（PD-1）和低水平的淋巴细胞活化基因3（LAG-3）。这表明高亲合力T细胞被募集到记忆池中，但在体外和体内可以通过超最佳刺激而丢失。其特征在于功能丧失和细胞死亡增加。剩余的CTL表现出低的功能亲合力，这反映在降低的抗肿瘤活性中。这可能导致免疫系统无法控制肿瘤的生长，并对疫苗接种策略和T细胞的过继转移产生影响。
High avidity cytotoxic T lymphocytes (CTL) are important in viral clearance and anti-tumor immunity, however, mechanisms for their optimal generation and maintenance in vivo remain unclear. Immunizing mice with an antibody-DNA vaccine encoding a single CTL epitope, induces a 100 fold higher avidity response than peptide vaccination with the identical epitope. The high avidity response is retained into memory and can be efficiently reactivated with an antibody-DNA boost. In contrast, reactivation of high avidity CTL with peptide, stimulated responses with a significant drop in avidity, suggesting loss or conversion of the high avidity CTL to lower avidity. Similarly, high avidity T cells maintained ex vivo were exquisitely sensitive to signaling with low doses of peptide (1 ng/ml) giving optimal TCR stimulation and resulting in retained avidity, proliferation and ability to kill specific targets. In contrast, high avidity T cells maintained ex vivo with supraoptimal TCR stimulation (10 µg/ml peptide) resulted in reduced avidity and failure to kill tumor cells. They also failed to proliferate, showed a significant increase in apoptosis and expressed high levels of the exhaustion marker programmed death-1 (PD-1) and low levels of the lymphocyte-activation gene 3 (LAG-3). This suggests high avidity T cells are recruited to the memory pool but can be lost by supraoptimal stimulation in vitro and in vivo. This is characterized by loss of function and an increase in cell death. The remaining CTL, exhibit low functional avidity that is reflected in reduced anti-tumor activity. This could contribute to failure of the immune system to control the growth of tumors and has implications for vaccination strategies and adoptive transfer of T cells.
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影响因子：
6.5
作者：
Chapon, Maxime;Randriamampita, Clotilde;Bercovici, Nadege
通讯作者：
Bercovici, Nadege
影响因子：
4.4
作者：
Cawthon, AG;Lu, HP;Alexander-Miller, MA
通讯作者：
Alexander-Miller, MA
影响因子：
4
作者：
HILL, AB;BLANDEN, RV;MULLBACHER, A
通讯作者：
MULLBACHER, A
影响因子：
15.3
作者：
Alexander-Miller, MA;Derby, MA;Berzofsky, JA
通讯作者：
Berzofsky, JA
DOI：
10.1084/jem.187.9.1383
发表时间：
1998-05-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gallimore A;Glithero A;Godkin A;Tissot AC;Plückthun A;Elliott T;Hengartner H;Zinkernagel R
通讯作者：
Zinkernagel R