PD-1 limits differentiation and plasticity of Tc17 cells

被引:6
作者
Arra, Aditya [1 ,2 ]
Lingel, Holger [1 ,2 ]
Pierau, Mandy [1 ,2 ]
Brunner-Weinzierl, Monika C. C. [1 ,2 ]
机构
[1] Otto von Guericke Univ, Univ Hosp, Dept Expt Pediat, Magdeburg, Germany
[2] Otto von Guericke Univ, Hlth Campus Immunol Infectiol & Inflammat, Magdeburg, Germany
来源
FRONTIERS IN IMMUNOLOGY | 2023年 / 14卷
关键词
T-cell differentiation; T-cell plasticity; Tc17; cells; cytotoxic T lymphocytes (CTLs); immune checkpoint; CD8(+) T-CELLS; FUNCTIONAL PLASTICITY; ANTI-PD-L1; ANTIBODY; PROGRAMMED DEATH-1; ADOPTIVE TRANSFER; CLINICAL ACTIVITY; SUPPRESSOR-CELLS; EFFECTOR; SAFETY; RESPONSES;
D O I
10.3389/fimmu.2023.1104730
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
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 ROR gamma t. 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-gamma, 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.
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页数:13
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