淋巴结中的分子、代谢和功能性CD4 T细胞麻痹阻碍了肿瘤的控制。
Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
发表日期：2023 Aug 30
作者：
Mengdi Guo, Diala Abd-Rabbo, Bruna C Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks
来源：
Cell Reports
摘要：
CD4 T细胞是抗癌免疫和免疫治疗的中心效应器，然而CD4肿瘤特异性T细胞（TTS细胞）的调节机制尚不清楚。我们证明 CD4 TTS细胞在肿瘤启动后很快被激活并开始分裂。然而，与CD8 TTS细胞或耗竭编程不同，CD4 TTS细胞的增殖被调节性T细胞和CTLA4的功能相互作用迅速冻结。这些机制共同使CD4 TTS细胞的分化瘫痪，重定代谢通路，并减少其在肿瘤中的积累。这种瘫痪状态在癌症进展过程中被积极维持，当抑制性约束减轻时，CD4 TTS细胞迅速恢复增殖和功能分化。克服其瘫痪状态可以建立长期的肿瘤控制，证明迅速瘫痪CD4 TTS细胞在肿瘤进展中的重要性，并展示了其作为治疗靶点的潜力。版权所有© 2023 作者。由Elsevier公司出版。保留所有权利。
CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.