肿瘤特异性CD8+ T细胞是抗肿瘤免疫的关键组成部分，然而，调节其表型和功能的因素尚未完全阐明。细胞因子IL-12和IL-27在促进CD8+ T细胞效应子功能并介导抗肿瘤反应方面扮演着重要角色。基于CD39的表面表达，可以鉴定特异性肿瘤CD8+浸润性淋巴细胞（TILs），而旁观者CD8+ TILs不表达这个酶。目前尚不清楚为什么肿瘤特异性CD8+ T细胞独特表达CD39。鉴于IL-12和IL-27在促进CD8+ T细胞功能方面的重要作用，我们探究了这些细胞因子是否能调节这些细胞上的CD39表达。通过体外刺激试验，我们确定小鼠脾CD8+ T细胞在存在IL-12和IL-27的情况下差异性上调CD39的表达。随后，我们评估了IL-12和IL-27诱导的CD39+CD8+ T细胞的耗竭特征。尽管在IL-12的激活下，CD39+CD8+ T细胞呈现出TIM-3+PD-1+LAG-3+共表达和降解能力降低的最高疲劳频率，但这些细胞仍能产生IFN-γ。IL-27诱导的CD39+CD8+ T细胞表达PD-1，但没有表现出终端疲劳表型。IL-27能够削弱CD39+CD8+ T细胞上IL-12介导的抑制性受体表达，但无法挽救去颗粒化能力。在免疫原性neuro-2a小鼠模型中，抑制IL-12活性降低了CD39+CD8+ TIL频率，但未改变整体CD8+ TIL频率。这些结果提供了关于CD8+ T细胞CD39表达的免疫调节因子的见解，并进一步突出了CD39诱导因子对CD8+ T细胞表型和效应功能的差异影响。Copyright © 2023 by The American Association of Immunologists, Inc.

Tumor-specific CD8+ T cells are critical components of antitumor immunity; however, factors that modulate their phenotype and function have not been completely elucidated. Cytokines IL-12 and IL-27 have recognized roles in promoting CD8+ T cells' effector function and mediated antitumor responses. Tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) can be identified based on surface expression of CD39, whereas bystander CD8+ TILs do not express this enzyme. It is currently unclear how and why tumor-specific CD8+ T cells uniquely express CD39. Given the important roles of IL-12 and IL-27 in promoting CD8+ T cell functionality, we investigated whether these cytokines could modulate CD39 expression on these cells. Using in vitro stimulation assays, we identified that murine splenic CD8+ T cells differentially upregulate CD39 in the presence of IL-12 and IL-27. Subsequently, we assessed the exhaustion profile of IL-12- and IL-27-induced CD39+CD8+ T cells. Despite the greatest frequency of exhausted CD39+CD8+ T cells after activation with IL-12, as demonstrated by the coexpression of TIM-3+PD-1+LAG-3+ and reduced degranulation capacity, these cells retained the ability to produce IFN-γ. IL-27-induced CD39+CD8+ T cells expressed PD-1 but did not exhibit a terminally exhausted phenotype. IL-27 was able to attenuate IL-12-mediated inhibitory receptor expression on CD39+CD8+ T cells but did not rescue degranulation ability. Using an immunogenic neuro-2a mouse model, inhibiting IL-12 activity reduced CD39+CD8+ TIL frequency compared with controls without changing the overall CD8+ TIL frequency. These results provide insight into immune regulators of CD39 expression on CD8+ T cells and further highlight the differential impact of CD39-inducing factors on the phenotype and effector functions of CD8+ T cells.Copyright © 2023 by The American Association of Immunologists, Inc.