Characteristics and functions of an atypical inflammation-associated GZMK+GZMB+CD8+ T subset in people living with HIV-1

• Published in: Molecular immunology Vol. 173; pp. 40 - 52
• Main Authors: Zhao, Liang, Wang, Huifang, Zhang, Yu, Shi, Yanze, Zhou, Chunbao, Yu, Minrui, Wang, Yanhu, Zhang, Liping, Xu, Zheng, Zhang, Ziying, Gao, Lingyu, Zhang, Jiyuan, Yang, Baopeng, Huang, Huihuang, Wang, Fu-Sheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2024
• Subjects: CD8+ T cell; GZMK; HIV-1 infection; Single-cell RNA sequencing; GZMK; HIV-1 infection; Single-cell RNA sequencing; CD8+ T cell; CD8(+) T cell
• ISSN: 0161-5890; 1872-9142; 1872-9142
• DOI: 10.1016/j.molimm.2024.07.003

HIV-1 chronically infects host CD4+ T lymphocytes and further affects a variety of immune cells, including CD8+ T cells. In our previous study, by analyzing unbiased high-dimensional single-cell RNA-seq data (scRNA-seq), we found that the frequency of GZMK+CD8+ T cells expressing granzyme K (GZMK) was increased in people living with HIV-1 (PLWHs). However, the phenotypic and functional characteristics of these cells in chronic HIV-1 infection and their correlation with disease are not well understood. In this study, we conducted a comprehensive analysis of scRNA-seq and matched T-cell receptor repertoire (TCR) sequencing data to delve into the characterizations of GZMK+CD8+ T cells, which was further validated by flow cytometry. We observed heterogeneity within the GZMK+CD8+ T cells, which could be further subdivided into a GZMK+GZMB- subset and a GZMK+GZMB+ subset, with the latter being significantly enriched in PLWHs. The GZMK+GZMB+ cells are a unique subset within CD8+ T cells, characterized by high proliferation, activation, inflammatory response, clone transition, etc., and are one of the differentiation endpoints by pseudotemporal analysis of CD8+αβ T cells. Despite being predominantly composed of effector memory T cells (Tem), similar to the GZMK+GZMB- subset, the GZMK+GZMB+ subset exhibits differentiation at a later stage than the GZMK+GZMB- subset. We also observed that the frequency/count of GZMK+GZMB+CD8+ T cells was negatively correlated with CD4/CD8 ratio, and positively correlated with HIV DNA, IP-10, and MIG levels in PLWHs. In vitro experiments demonstrate that GZMK can potentiate the stimulatory effects of lipopolysaccharide (LPS) on THP-1 macrophages via the TLR-4 pathway, significantly enhancing the secretion of IP-10, MIG, and MCP-1, as well as increasing the proportion of TNF-α+ cells. In conclusion, in PLWHs, GZMK+GZMB+CD8+ T cells are a highly reactive and inflammatory-inducing subset that may be associated with systemic inflammation. •We characterized GZMK+CD8+ T cells and identified a new subset in HIV-1 patients.•We used scRNA-seq, TCR-seq, flow cytometry, and functional experiments.•The GZMK+GZMB+ subset is a subset of GZMK+ T cells that is enriched in HIV-1 patients.•The GZMK+GZMB+ subset is characterized by proliferation, activation, inflammation.•The GZMK+GZMB+ subset is highly reactive and associated with systemic inflammation.