Frontiers in Immunology | |
PD-1 limits differentiation and plasticity of Tc17 cells | |
Immunology | |
Aditya Arra1  Holger Lingel1  Monika C. Brunner-Weinzierl1  Mandy Pierau1  | |
[1] Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany;Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany; | |
关键词: T-cell differentiation; T-cell plasticity; Tc17 cells; cytotoxic T lymphocytes (CTLs); immune checkpoint; | |
DOI : 10.3389/fimmu.2023.1104730 | |
received in 2022-11-22, accepted in 2023-04-05, 发布年份 2023 | |
来源: Frontiers | |
【 摘 要 】
Blockade of surface co-inhibitory receptor programmed cell death-1 (PD-1; CD279) has been established as an important immunotherapeutic approach to treat malignancies. On a cellular level, PD-1 is demonstrated to be of particular importance in inhibiting differentiation and effector function of cytotoxic Tc1 cells (CTLs). Nevertheless, the role of PD-1 in modulating interleukin (IL)-17-producing CD8+ T-cells (Tc17 cells), which generally display suppressed cytotoxic nature, is not well understood. To evaluate the impact of PD-1 in Tc17 responses, we examined its functioning using different in vitro and in vivo models. Upon activation of CD8+ T-cells in Tc17 environment, we found that PD-1 was rapidly expressed on the surface of CD8+ T-cells and triggered a T-cell-internal mechanism that inhibited the expression of IL-17 and Tc17-supporting transcription factors pSTAT3 and RORγt. Expression of type17-polarising cytokine IL-21 and the receptor for IL-23 were also suppressed. Intriguingly, adoptively transferred, PD-1-/- Tc17 cells were highly efficient in rejection of established B16 melanoma in vivo and displayed Tc1 like characteristics ex vivo. When using IL-17A-eGFP reporter mice for in vitro fate tracking, IL-17A-eGFP expressing cells lacking PD-1 signaling upon re-stimulation with IL-12 quickly acquired Tc1 characteristics such as IFN-γ, and granzyme B expression, implicating lineage independent upregulation of CTL-characteristics that are needed for tumor control. In line with plasticity characteristics, absence of PD-1 signaling in Tc17 cells increased the expression of the stemness and persistence-associated molecules TCF1 and BCL6. Thus, PD-1 plays a central role in the specific suppression of Tc17 differentiation and its plasticity in relation to CTL-driven tumor rejection, which provides further explanation as to why the blockade of PD-1 is such an efficient therapeutic target for inducing tumor rejection.
【 授权许可】
Unknown
Copyright © 2023 Arra, Lingel, Pierau and Brunner-Weinzierl
【 预 览 】
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