Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells.,Immunity

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Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells.
Immunity ( IF 25.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.immuni.2019.12.007
Anna Śledzińska ₁ , Maria Vila de Mucha ₂ , Katharina Bergerhoff ₁ , Alastair Hotblack ₃ , Dafne Franz Demane ₁ , Ehsan Ghorani ₁ , Ayse U Akarca ₄ , Maria A V Marzolini ₁ , Isabelle Solomon ₁ , Frederick Arce Vargas ₁ , Martin Pule ₃ , Masahiro Ono ₅ , Benedict Seddon ₆ , George Kassiotis ₇ , Charlotte E Ariyan ₈ , Thomas Korn ₉ , Teresa Marafioti ₄ , Graham M Lord ₁₀ , Hans Stauss ₆ , Richard G Jenner ₁₁ , Karl S Peggs ₁ , Sergio A Quezada ₁

Affiliation

Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK.
Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK.
Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK.
Faculty of Natural Sciences, Department of Life Sciences, Imperial College London, London SW7 2BB, UK.
Institute of Immunity and Transplantation, Department of Immunology, Royal Free Hospital, London NW3 2PF, UK.
Retroviral Immunology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Memorial Sloan Kettering Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Faculty of Biology, Medicine and Health, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK.

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.

中文翻译：

调节性 T 细胞抑制 CD4+ T 细胞依赖白细胞介素 2 和 Blimp-1 获得细胞毒性功能。

除了辅助和调节潜力外，CD4+ T 细胞还获得以颗粒酶 B (GzmB) 表达为标志的细胞毒活性以及促进对已形成肿瘤的排斥的能力。在这里，我们研究了免疫治疗后细胞毒性 CD4+ T 细胞分化的分子和细胞机制。 CD4+ 转移至淋巴细胞清除的动物或调节性 T (Treg) 细胞清除可通过肿瘤浸润 CD4+ 促进 GzmB 表达，而白介素 2 (IL-2) 中和可阻止这种情况的发生。转录分析揭示了多功能辅助细胞和细胞毒性表型，其特征是转录因子 T-bet 和 Blimp-1 的表达。虽然 T-bet 消融限制了干扰素-γ (IFN-γ) 的产生，但 Blimp-1 的缺失阻止了响应 IL-2 的 GzmB 表达，这表明肿瘤反应性 CD4+ T 细胞的多功能性需要两个独立的程序。我们的研究结果强调了 Treg 细胞、IL-2 和 Blimp-1 在控制细胞毒性 CD4+ T 细胞分化中的作用，并提供了通过操纵它们来增强抗肿瘤活性的途径。

更新日期：2020-01-07

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