Granzyme A Produced by γ9δ2 T Cells Activates ER Stress Responses and ATP Production, and Protects Against Intracellular Mycobacterial Replication Independent of Enzymatic Activity

Frontiers in Immunology

Michael Walch¹  Niels Bovenschen²  David C. Wood³  Nicola Pozzi³  Mei Xia⁴  Rachel L. Edwards⁴  Valerio Rasi⁴  Christopher S. Eickhoff⁴  Daniel F. Hoft⁴ 

[1] Anatomy Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland;Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands;Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, United States;Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States;Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States;Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands;

关键词: Granzyme A;    Mycobacterium tuberculosis;    BCG;    ER stress response;    ATP production;    2D-DIGE;   

DOI  :  10.3389/fimmu.2021.712678

来源: DOAJ

【 摘 要 】

Mycobacterium tuberculosis (Mtb), the pathological agent that causes tuberculosis (TB) is the number one infectious killer worldwide with one fourth of the world’s population currently infected. Data indicate that γ9δ2 T cells secrete Granzyme A (GzmA) in the extracellular space triggering the infected monocyte to inhibit growth of intracellular mycobacteria. Accordingly, deletion of GZMA from γ9δ2 T cells reverses their inhibitory capacity. Through mechanistic studies, GzmA’s action was investigated in monocytes from human PBMCs. The use of recombinant human GzmA expressed in a mammalian system induced inhibition of intracellular mycobacteria to the same degree as previous human native protein findings. Our data indicate that: 1) GzmA is internalized within mycobacteria-infected cells, suggesting that GzmA uptake could prevent infection and 2) that the active site is not required to inhibit intracellular replication. Global proteomic analysis demonstrated that the ER stress response and ATP producing proteins were upregulated after GzmA treatment, and these proteins abundancies were confirmed by examining their expression in an independent set of patient samples. Our data suggest that immunotherapeutic host interventions of these pathways may contribute to better control of the current TB epidemic.

【 授权许可】

Unknown