Phosphoantigen-Stimulated γδ T Cells Suppress Natural Killer-Cell Responses to Missing-Self.
Phosphoantigen-Stimulated γδ T Cells Suppress Natural Killer-Cell Responses to Missing-Self.
复制标题
磷酸化抗原刺激的γδ T细胞抑制自然杀伤细胞对缺失自我的反应。
DOI：
10.1158/2326-6066.cir-21-0696
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发表时间：
2022-05-03
影响因子：
10.1
通讯作者：
Djaoud, Zakia
中科院分区：
文献类型：
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作者：
Walwyn-Brown, Katherine;Pugh, Jason;Cocker, Alexander T. H.;Beyzaie, Niassan;Singer, Bernhard B.;Olive, Daniel;Guethlein, Lisbeth A.;Parham, Peter;Djaoud, Zakia
由磷酸化抗原（pAg）刺激的γδ T细胞是分泌Th 1细胞因子并杀死肿瘤细胞的有效效应器。因此，它们被认为是用于癌症免疫治疗的候选者。然而，它们在几项临床试验中仅被证明是中等有效的。我们研究了pAg刺激的γδ T细胞与自然杀伤（NK）细胞和CD 8 + T细胞（分别是主要的先天性和适应性效应器）相互作用的后果。我们发现，pAg刺激的γδ T细胞抑制NK细胞对“缺失自我”的反应，但对抗原特异性CD 8 + T细胞反应没有影响。对分泌的细胞因子的广泛分析表明，pAg刺激的γδ T细胞具有促炎特征。用pAg刺激的γδ T细胞致敏的CMV-pp 65特异性CD 8 + T细胞对负载pp 65的靶细胞的应答几乎没有影响。相比之下，用γδ T细胞类似地致敏的NK细胞在响应HLA I类缺陷靶点时去免疫和产生IFNγ的能力受损。这种作用依赖于BTN 3A 1，并且需要NK细胞和γδ T细胞之间的直接接触。NK细胞的γδ T细胞致敏也导致NK细胞上NKG 2D和NKp 44的下调。每个NK细胞亚群都受到γδ T细胞介导的免疫抑制的影响，但对KIR+ NKG 2A − NK细胞的影响最大。因此，我们报告了γδ T细胞的一个先前未知的功能，作为NK细胞对“丢失自我”反应的制动器。这为优化γδ T细胞在癌症免疫治疗中的使用以及评估它们在对产生pAg的病原体的免疫应答中的作用提供了新的视角。
γδ T cells stimulated by phosphoantigens (pAg) are potent effectors that secrete Th1 cytokines and kill tumor cells. Consequently, they are considered candidates for use in cancer immunotherapy. However, they have proven only moderately effective in several clinical trials. We studied the consequences of pAg-stimulated γδ T-cell interactions with Natural Killer (NK) cells and CD8+ T cells, major innate and adaptive effectors, respectively. We found that pAg-stimulated γδ T cells suppressed NK-cell responses to “missing-self” but had no effect on antigen-specific CD8+ T-cell responses. Extensive analysis of the secreted cytokines showed that pAg-stimulated γδ T cells had a pro-inflammatory profile. CMV-pp65–specific CD8+ T cells primed with pAg-stimulated γδ T cells showed little effect on responses to pp65-loaded target cells. By contrast, NK cells primed similarly with γδ T cells had impaired capacity to degranulate and produce IFNγ in response to HLA class I–deficient targets. This effect depended on BTN3A1 and required direct contact between NK cells and γδ T cells. γδ T cell–priming of NK cells also led to a downregulation of NKG2D and NKp44 on NK cells. Every NK-cell subset was affected by γδ T cell–mediated immunosuppression, but the strongest effect was on KIR+NKG2A− NK cells. We therefore report a previously unknown function for γδ T cells, as brakes of NK-cell responses to “missing-self”. This provides a new perspective for optimizing the use of γδ T cells in cancer immunotherapy and for assessing their role in immune responses to pAg-producing pathogens.