2020年1月7日，英国伦敦大学学院Sergio A. Quezada、Karl S. Peggs等研究人员合作在《免疫》在线发表论文。他们的研究发现，调节性T细胞抑制CD4⁺T细胞对白细胞介素2和Blimp-1依赖性细胞毒功能的获得。

他们研究了免疫疗法后促进细胞毒性CD4⁺T细胞分化的分子和细胞机制。CD4⁺细胞转移到淋巴去除的动物中或者调节性T（Treg）细胞耗竭可通过肿瘤浸润性CD4⁺促进颗粒酶B（GzmB）表达，而白介素2（IL-2）中和可防止这种情况。转录分析揭示了一种多功能的辅助和细胞毒性表型，其特征在于转录因子T-bet和Blimp-1的表达。尽管T-bet敲除限制了干扰素-γ（IFN-γ）的产生，但是Blimp-1的缺失阻止了对IL-2的GzmB表达，这表明肿瘤反应性CD4⁺T细胞的多能性需要两个独立的调控程序。这些发现强调了Treg细胞、IL-2和Blimp-1在调控细胞毒性CD4⁺T细胞分化中的作用，并提供了通过其操纵来增强抗肿瘤活性的途径。

研究人员表示，除了辅助和调节潜力外，CD4⁺T细胞还具有以GzmB表达为标志的细胞毒性活性，并具有促进肿瘤排斥的能力。

附：英文原文

Title: Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

Author: Anna ledzińska, 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 Pule, Masahiro Ono, Benedict Seddon, George Kassiotis, Charlotte E. Ariyan, Thomas Korn, Teresa Marafioti, Graham M. Lord, Hans Stauss, Richard G. Jenner, Karl S. Peggs, Sergio A. Quezada

Issue&Volume: January 7, 2020

Abstract: In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression andthe ability to promote rejection of established tumors. Here, we examined the molecularand cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promotedGzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysisrevealed a polyfunctional helper and cytotoxic phenotype characterized by the expressionof 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-reactiveCD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controllingthe differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.

DOI: 10.1016/j.immuni.2019.12.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30526-6