Human γδ T-Cell Control of Mucosal immunity and inflammation

Human gamma delta 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 gamma delta T-cell compartment includes multiple subsets with highly flexible effector functions, human mucosal tissues are dominated by host stress-responsive V delta 1(+) T-cells and microbe-responsive V delta 2(+) T-cells. Widely recognized for their potent cytotoxicity, emerging data suggest that gamma delta 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 gamma delta T-cells. Indeed, several drugs already in clinical use, including vedolizumab, infliximab, and azathioprine, likely owe their efficacy in part to modulation of gamma delta T-cell function. Recent clinical trials of V delta 2(+) 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 gamma delta 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 gamma delta 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 gamma delta T-cell-based therapies.