T细胞
白细胞介素2受体
效应器
白细胞介素21
CD8型
白细胞介素15
T细胞受体
白细胞介素12
癌症研究
抗原提呈细胞
免疫系统
分子生物学
作者
Anna Śledzińska,Maria Vila de Mucha,Katharina Bergerhoff,Alastair Hotblack,Dafne Franz Demane,Ehsan Ghorani,Ayse U. Akarca,Maria A V Marzolini,Isabelle Solomon,Frederick Arce Vargas,Martin Pulè,Masahiro Ono,Benedict Seddon,George Kassiotis,Charlotte E. Ariyan,Thomas Korn,Teresa Marafioti,Graham M. Lord,Hans J. Stauss,Richard G. Jenner,Karl S. Peggs,Sergio A. Quezada
出处
期刊:Immunity
[Elsevier]
日期:2020-01-01
卷期号:52 (1): 151-166.e6
被引量:118
标识
DOI:10.1016/j.immuni.2019.12.007
摘要
In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.
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