Abstract
Human γδ T-cells include some of the most common “antigen-specific” cell types in peripheral blood and are enriched yet further at mucosal barrier sites where microbial infection and tumors often originate. While the γδ T-cell compartment includes multiple subsets with highly flexible effector functions, human mucosal tissues are dominated by host stress-responsive Vδ1+ T-cells and microbe-responsive Vδ2+ T-cells. Widely recognized for their potent cytotoxicity, emerging data suggest that γδ T-cells also exert strong influences on downstream adaptive immunity to pathogens and tumors, in particular via activation of antigen-presenting cells and/or direct stimulation of other mucosal leukocytes. These unique functional attributes and lack of MHC restriction have prompted considerable interest in therapeutic targeting of γδ T-cells. Indeed, several drugs already in clinical use, including vedolizumab, infliximab, and azathioprine, likely owe their efficacy in part to modulation of γδ T-cell function. Recent clinical trials of Vδ2+ T-cell-selective treatments indicate a good safety profile in human patients, and efficacy is set to increase as more potent/targeted drugs continue to be developed. Key advances will include identifying methods of directing γδ T-cell recruitment to specific tissues to enhance host protection against invading pathogens, or alternatively, retaining these cells in the circulation to limit peripheral inflammation and/or improve responses to blood malignancies. Human γδ T-cell control of mucosal immunity is likely exerted via multiple mechanisms that induce diverse responses in other types of tissue-resident leukocytes. Understanding the microenvironmental signals that regulate these functions will be critical to the development of new γδ T-cell-based therapies.
Highlights
The γδ T-cell compartment includes some of the most numerous “antigen-specific” cell types in peripheral blood and is enriched yet further in mucosal tissues including the lung and intestine [1, 2]
T-cells in human intestine modulates cytokine production by colonic αβ T-cells in the same piece of gut tissue [55], indicating that these cells are present in sufficient numbers to exert potent effects on downstream mucosal immunity
Therapeutic antibody-mediated disruption of Th17 biology led to increased mucosal inflammation in patients with Crohn’s disease during randomized controlled trials [74, 75], suggesting that Vδ2+ T-cell-directed immunotherapies might prove to be an effective method of enhancing barrier protection without impacting on mucosal levels of IL-17
Summary
The γδ T-cell compartment includes some of the most numerous “antigen-specific” cell types in peripheral blood and is enriched yet further in mucosal tissues including the lung and intestine [1, 2]. Consistent with a role for γδ-IEL in monitoring gut barrier function, recent data indicate that these cells are highly motile in the mouse intestine and actively scan the epithelium for signs of cellular stress, with pro-inflammatory cytokines and/or pathogen encounter significantly modulating this behavior [14, 15].
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