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Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches
Immunity ( IF 32.4 ) Pub Date : 2022-04-01 , DOI: 10.1016/j.immuni.2022.03.006
Sabrina Dähling 1 , Ana Maria Mansilla 2 , Konrad Knöpper 3 , Anika Grafen 3 , Daniel T Utzschneider 4 , Milas Ugur 3 , Paul G Whitney 4 , Annabell Bachem 4 , Panagiota Arampatzi 5 , Fabian Imdahl 6 , Tsuneyasu Kaisho 7 , Dietmar Zehn 8 , Frederick Klauschen 9 , Natalio Garbi 10 , Axel Kallies 4 , Antoine-Emmanuel Saliba 6 , Georg Gasteiger 3 , Sammy Bedoui 4 , Wolfgang Kastenmüller 3
Affiliation  

Reinvigoration of exhausted CD8+ T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control. cDC1s were dispensable for Tpex cell expansion but provided an essential niche to promote Tpex cell maintenance, preventing their overactivation and T-cell-mediated immunopathology. Mechanistically, cDC1s insulated Tpex cells via MHC-I-dependent interactions to prevent their activation within other inflammatory environments that further aggravated their exhaustion. Our findings reveal that cDC1s maintain and safeguard Tpex cells within distinct anatomical niches to balance viral control, exhaustion, and immunopathology.



中文翻译:

1型常规树突状细胞维持和指导不同细胞生态位中耗尽的T细胞前体的分化

重振疲惫的CD8 +检查点免疫疗法的 T (Tex) 细胞依赖于耗尽的 T (Tpex) 细胞前体的激活,但它们的维持、分化和与其他细胞相互作用的局部解剖学背景尚不清楚。在这里,我们确定了转录上不同的 Tpex 亚群,通过向 Tex 细胞的过渡细胞状态绘制了它们的分化轨迹,并将这些细胞状态定位到特定的脾小生境。常规树突状细胞 (cDC) 对于成功的 αPD-L1 治疗至关重要,并且需要介导病毒控制。cDC1s 对于 Tpex 细胞扩增是可有可无的,但提供了促进 Tpex 细胞维持、防止其过度活化和 T 细胞介导的免疫病理学的必要生态位。机械地,cDC1s 通过依赖 MHC-I 的相互作用隔离 Tpex 细胞,以防止它们在其他炎症环境中激活,从而进一步加剧它们的衰竭。我们的研究结果表明,cDC1s 在不同的解剖生态位中维持和保护 Tpex 细胞,以平衡病毒控制、衰竭和免疫病理学。

更新日期:2022-04-01
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