CD137 expression and signal function drive pleiotropic γδ T-cell effector functions that inhibit intracellular M. tuberculosis growth

• Published in: Clinical immunology (Orlando, Fla.) Vol. 266; p. 110331
• Main Authors: Ji, Xuejiao, Huang, Guixian, Peng, Ying, Wang, Juechu, Cai, Xia, Yang, Enzhuo, Zhu, Liying, Wu, Yuan, Sha, Wei, Wang, Feifei, Shen, Ling, Shen, Hongbo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Adult; Animals; Anti-tuberculosis activity; Antigens, Bacterial - immunology; CD137; Cytokines - immunology; Cytokines - metabolism; Female; GM-CSF; Humans; Lymphocyte Activation - immunology; Macrophages - immunology; Male; Mice; Mice, SCID; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Signal Transduction - immunology; Tuberculosis - immunology; Tuberculosis - microbiology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; γδ T cells; γδ T cells; Anti-tuberculosis activity; CD137; Mycobacterium tuberculosis; GM-CSF
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2024.110331

Co-activation signal that induces/sustains pleiotropic effector functions of antigen-specific γδ T cells remains unknown. Here, Mycobacteria tuberculosis (Mtb) tuberculin administration during tuberculosis (TB) skin test resulted in rapid expression of co-activation signal molecules CD137 and CD107a by fast-acting Vγ2Vδ2 T cells in TB-resistant subjects (Resisters), but not patients with active TB. And, anti-CD137 agonistic antibody treatment experiments showed that CD137 signaling enabled Vγ2Vδ2 T cells to produce more effector cytokines and inhibit intracellular Mtb growth in macrophages (Mɸ). Consistently, Mtb antigen (Ag) HMBPP stimulation induced sustainable high-level CD137 expression in fresh and activated Vγ2Vδ2 T cells from uninfected subjects, but not TB patients. CD137+Vγ2Vδ2 T-cell subtype predominantly displayed central memory phenotype and mounted better proliferative responses than CD137−Vγ2Vδ2 T-cells. In response to HMBPP, CD137+Vγ2Vδ2 T-cell subtype rapidly differentiated into greater numbers of pleiotropic effector cells producing anti-Mtb cytokines compared to CD137−Vγ2Vδ2 T subtype, with the non-canonical NF-κB pathway involved. CD137 expression in Vγ2Vδ2 T cells appeared to signal anti-Mtb effector functions leading to intracellular Mtb growth inhibition in Mɸ, and active TB disrupted such CD137-driven anti-Mtb effector functions. CD137+Vγ2Vδ2 T-cells subtype exhibited an epigenetic-driven high-level expression of GM-CSF and de novo production of GM-CSF critical for Vγ2Vδ2 T-cell controlling of Mtb growth in Mϕ. Concurrently, exosomes produced by CD137+Vγ2Vδ2 T cells potently inhibited intracellular mycobacterial growth. Furthermore, adoptive transfer of human CD137+Vγ2Vδ2 T cells to Mtb-infected SCID mice conferred protective immunity against Mtb infection. Thus, our data suggest that CD137 expression/signaling drives pleiotropic γδ T-cell effector functions that inhibit intracellular Mtb growth.