Integrated single-cell transcriptome and T cell receptor profiling reveals defects of T cell exhaustion in pulmonary tuberculosis

• Published in: The Journal of infection Vol. 88; no. 6; p. 106158
• Main Authors: Wen, Zilu, Wang, Lin, Ma, Hui, Li, Leilei, Wan, Laiyi, Shi, Lei, Li, Hongwei, Chen, Hui, Hao, Wentao, Song, Shu, Xue, Qinghua, Wei, Yutong, Li, Feng, Xu, Jianqing, Zhang, Shulin, Wong, Ka-Wing, Song, Yanzheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2024
• Subjects: Chronic inflammation; Immunotherapy; Single-cell RNA sequencing; T cell exhaustion; Tuberculosis; T cell exhaustion; Tuberculosis; Chronic inflammation; Single-cell RNA sequencing; Immunotherapy
• ISSN: 0163-4453; 1532-2742
• DOI: 10.1016/j.jinf.2024.106158

Tuberculosis-affected lungs with chronic inflammation harbor abundant immunosuppressive immune cells but the nature of such inflammation is unclear. Dysfunction in T cell exhaustion, while implicated in chronic inflammatory diseases, remains unexplored in tuberculosis. Given that immunotherapy targeting exhaustion checkpoints exacerbates tuberculosis, we speculate that T cell exhaustion is dysfunctional in tuberculosis. Using integrated single-cell RNA sequencing and T cell receptor profiling we reported defects in exhaustion responses within inflamed tuberculosis-affected lungs. Tuberculosis lungs demonstrated significantly reduced levels of exhausted CD8+ T cells and exhibited diminished expression of exhaustion-related transcripts among clonally expanded CD4+ and CD8+ T cells. Additionally, clonal expansion of CD4+ and CD8+ T cells bearing T cell receptors specific for CMV was observed. Expanded CD8+ T cells expressed the cytolytic marker GZMK. Hence, inflamed tuberculosis-affected lungs displayed dysfunction in T cell exhaustion. Our findings likely hold implications for understanding the reactivation of tuberculosis observed in patients undergoing immunotherapy targeting the exhaustion checkpoint. •Single-cell analysis revealed defective T cell exhaustion in TB lungs.•Clonal expansion of T cells in TB linked to diminished exhaustion responses.•CMV-reactive clonally expanded T cells were enriched in TB lungs.•Upregulated GZMK, IFNγ in precursor of exhausted CD8+ T cells in TB lungs.•Dysfunctional T cell exhaustion may contribute to TB immunopathology.