Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.
Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.
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DOI：
10.1016/j.vaccine.2015.06.070
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发表时间：
2015-07-31
期刊：
影响因子：
5.5
通讯作者：
Rosenberg AS
中科院分区：
文献类型：
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作者：
McFarland HI;Berkson JD;Lee JP;Elkahloun AG;Mason KP;Rosenberg AS
亚致死剂量γ照射可消除CD8+T细胞介导的记忆反应。在这项工作中，我们探索了如何在这种暴露之后拯救这些记忆反应。我们利用了两种CD8+T细胞介导的免疫模型：一种是单核细胞增多性李斯特氏菌(List)感染的小鼠模型，在该模型中可以追踪针对L8+T细胞表达的抗原(Listeriolysin O，LLO)的CD8+T细胞；另一种是小鼠皮肤移植模型，在该模型中CD8+T细胞介导了跨越MHC I类(DD)差异的排斥反应。在LM免疫的小鼠中，LL0特异性CD8+T记忆细胞在照射后1-3天丢失，并用减毒株快速重新免疫保存，这些小鼠在随后的野生型LM攻击中存活下来。一个遗传的“救援信号”确定了一组在辐射和救援后维持或上调的免疫相关的mRNA。其中许多因子，包括IL-36γ、Dectin-2(Clec4n)和mir101c，在小鼠单独暴露于亚致死γ辐射后迅速上调，并在早期维持，但不是在以后的救援中。这些因素将被评估为潜在的治疗方法，以取代单个疫苗，在亚致死性γ照射后全球挽救CD8+T记忆细胞反应。同种异体皮肤移植模型与同种异体皮肤移植模型的相似之处在于，在γ亚致死剂量照射的小鼠中，同种异体皮肤移植的加速排斥反应消失，但输注表达同种异体DD的骨髓细胞1-4天PI保存了γ+T记忆介导的加速排斥反应，进一步提示先天免疫反应可能并不总是拯救CD8+记忆T细胞所必需的。
Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (Dd) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic “signature of rescue” identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated Dd skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic Dd expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation.