Harnessing Mycobacterium tuberculosis–Expanded γδ T-Cells for Tuberculosis Immunotherapy: Emerging Immunological Perspectives

γδ T Cells in Tuberculosis Immunotherapy

Abstract

The rising incidence of multidrug-resistant and extensively drug-resistant tuberculosis and the persistent syndemic interaction between Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus have substantially intensified the global tuberculosis burden. These challenges have renewed scientific interest in understanding the immunological mechanisms that regulate host resistance, as well as the sophisticated virulence strategies employed by Mtb. Tuberculosis infection is typically initiated through inhalation of aerosolized bacilli, which are first encountered by alveolar macrophages within the pulmonary microenvironment. Acting as frontline immunological sentinels, these cells recognize conserved microbial patterns through diverse pattern-recognition receptors—including Toll-like receptors, C-type lectin receptors, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin, and nucleotide-binding oligomerization domain-like receptors—thereby activating intracellular antimicrobial and inflammatory signaling pathways. Although tuberculosis immunology has been extensively investigated, earlier reviews have largely focused on conventional immune pathways, providing comparatively limited attention to the immunotherapeutic potential of Mtb–expanded gamma delta (γδ) T-cells. A comprehensive synthesis addressing their expansion mechanisms, immunomodulatory functions, and translational significance in tuberculosis immunotherapy remains insufficiently explored. Consequently, a focused evaluation of the emerging role of γδ T-cells in host defense against tuberculosis is warranted. This review provides an integrated overview of the immunological functions and therapeutic relevance of γδ T-cells in tuberculosis. It discusses the role of γδ T-cells during Mtb infection, emphasizing their early antimicrobial responses and their contribution to innate-like immunity. The review further examines the interactions between γδ T-cells and dendritiC-cells, highlighting their cooperative role in antigen presentation and immune modulation. The mechanisms underlying γδ T-cell activation, interactions, and maturation during Mtb infection are addressed. Finally, emerging γδ T-cell–based immunotherapeutic strategies are being explored as potential host-directed approaches to complement conventional tuberculosis treatment. By consolidating recent advances in γδ T-cell biology and in understanding their role in tuberculosis immunity, this review addresses existing gaps in the literature and underscores their potential as targets for innovative therapeutic interventions against increasingly drug-resistant tuberculosis.