From Host Defense to Metabolic Signatures: Unveiling the Role of γδ T Cells in Bacterial Infections

Abstract

The growth of antibiotic-resistant bacterial infections necessitates focusing on host-derived immunotherapies. γδ T cells are an unconventional T cell subset, making up a relatively small portion of healthy circulating lymphocytes but a substantially increased proportion in mucosal and epithelial tissues. γδ T cells are activated and expanded in response to bacterial infection, having the capability to produce proinflammatory cytokines to recruit neutrophils and clear infection. They also play a significant role in dampening immune response to control inflammation and protecting the host against secondary challenge, making them promising targets when developing immunotherapy. Importantly, γδ T cells have differential metabolic states influencing their cytokine profile and subsequent inflammatory capacity. Though these differential metabolic states have not been well studied or reviewed in the context of bacterial infection, they are critical in understanding the mechanistic underpinnings of the host's innate immune response. Therefore, this review will focus on the context-specific host defense conferred by γδ T cells during infection with Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, and Mycobacterium tuberculosis.

Keywords: bacterial infection; immunometabolism; γδ T cells.

Figure 1

Immune metabolism of γδ T cells. (A) CD27+ γδ T cells are ligand-experienced and splenic resident. They undergo glycolysis after thymic development and release IFNγ. CD27− γδ T cells, however, are ligand naive and lymph node resident. They undergo oxidative phosphorylation, governed by c-Maf regulation of rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) and Th17 cytokine-producing genes Rorc, Il17a, and Blk. (B) In inflammatory psoriasis, basal keratinocytes produce oxysterols through the enzyme cholesterol-25-hydroxylase (CH25H). The oxysterols are ligands for the G-protein-coupled receptor GPR183 on γδ T cells. Subsequent lipid metabolism and signaling leads to IL-17 release and inflammation. In a mouse model, dietary cholesterol contributes to this signaling cascade, worsening psoriasis. (C) During psoriasis, γδ T cells undergo glutaminolysis, promoting subsequent acetylation of the Il17a promoter and releasing IL-17, increasing inflammation. CD69 and LAT1 expression on γδ T cells promote tryptophan uptake and metabolism in psoriasis. The resulting Ahr signaling cascade leads to IL-22 release and increased inflammation.

Figure 2

Role of γδ T cells during cutaneous S. aureus infection. Intradermal S. aureus infection and subsequent IL-1β signaling stimulate cutaneous γδ T cells to produce proinflammatory cytokines IFNy, TNFα, IL-22, and IL-17. These cytokines contribute to neutrophil recruitment, production of antimicrobial peptides, skin inflammation, and eventual bacterial clearance. Commensal S. epidermidis, skin colonization, stimulates γδ T cells to produce perforin-2, a pore-forming cytolysin that helps clear S. aureus infection.