Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8⁺ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8⁺ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.

枯否细胞 (KCs) 是高度丰富的血管内肝脏驻留巨噬细胞，以其清道夫和吞噬功能而闻名。KCs 还可以将抗原呈递给 CD8 ⁺ T 细胞并促进耐受或效应分化，但对这些差异结果背后的机制知之甚少。在这里，我们使用了乙型肝炎病毒 (HBV) 感染的小鼠模型，其中 HBV 特异性幼稚 CD8 ⁺识别肝细胞抗原的 T 细胞被驱动进入免疫功能障碍状态，以识别在白细胞介素 2 (IL-2) 给药后交叉呈递肝细胞抗原的 KC 子集（称为 KC2），从而提高 T 细胞的抗病毒功能细胞。从包括 KC2 在内的所有 KC 中去除 MHC-I 或选择性消耗 KC2 会损害 IL-2 恢复由肝内启动诱导的 T 细胞功能障碍的能力。总之，通过感知 IL-2 和交叉呈递肝细胞抗原，KC2 克服了肝脏微环境的耐受性潜能，为增强肝脏 T 细胞免疫提供了新的策略。