慢性感染和癌症通过诱导T细胞衰竭的机制逃避宿主免疫系统，表现出异质性。衰竭的CD8+ T细胞群体中Tpex和Tex细胞的存在揭示了干细胞样祖细胞和终末衰竭性维持发育的重要性，然而其发育机制目前尚不完全了解。在本研究中，我们报道了高流动群组盒2 (HMGB2) 蛋白对衰竭的CD8+ T细胞表达上调并持续，以及HMGB2表达对其分化的关键性。通过表观遗传和转录编程，我们确定了HMGB2作为Tpex细胞分化和维持的细胞内调节因子，在慢性病毒感染和肿瘤中发挥作用。尽管Hmgb2-/- CD8+ T细胞表达TCF-1和TOX，这些主要调控因子却无法维持Tpex细胞在持续抗原刺激下的分化和长期存活。此外，在急性病毒感染后，HMGB2也在记忆CD8+ T细胞的分化和功能中起到细胞内调节作用。我们的研究结果表明，HMGB2是CD8+ T细胞的关键调节因子，可能是未来T细胞免疫疗法的重要分子靶点。© 2023. Springer Nature Limited.

Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2-/- CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.© 2023. Springer Nature Limited.