Abstract
The skin contains many resident immune cells that play key roles in tissue homeostasis. In mouse skin, Vγ5Vδ1+ T cells have the innate-like capacity to respond rapidly and in large numbers to markers of tissue stress, rather than requiring clonal, antigen-specific activation. This lymphoid stress surveillance response (LSSR) is key to host immunity, contributing to barrier integrity and cutaneous atopic responses. In this thesis, we have sought to identify if the potential for LSSR exists in human skin. Our key and novel findings are a revised assessment of the lymphocyte content of human skin, with the discovery that the predominant γδ T cell population shows innate-like responsiveness analogous to that in the murine epidermis.Through the adaptation of a novel skin explant protocol, we have established that the skin contains a distinct and reproducible population of γδ T cells, which predominantly express the Vδ1 and Vδ3 TCR chains. These cells displayed features of tissue-resident “memory” TCRαβ+ [TRM] cells, but strikingly had the capacity to become activated by ligands for the NKG2D receptor, seemingly independent of TCR antigen receptor signalling. Such responsiveness was not seen in other NKG2D+ T cell subsets. Upon such NKG2D-mediated activation skin-resident γδ T cells showed robust effector responses, producing TNFα, IFNg, cytolytic mediators and additional growth factors/chemokines. Such innate-like responsiveness was dependent on both PI3K and calcineurin activity, but independent of Lck, characterising this novel mode of innate-like T cell activation. Skin-derived γδ T cells also showed profound cytolytic activity against transformed epithelial cells in vitro, which was in part dependent on NKG2D, demonstrating the functional potential of these cells in tissue stress-surveillance.
These data provide the first clear identification of a human innate-like T cell subset, locating them in the tissue immune compartment. This strongly argues for the existence of LSSR in human tissues and places skin-resident γδ T cells in the early afferent phase of the immune response. This offers a new perspective on tissue immune surveillance and has implications for future studies in human skin immunobiology.
| Date of Award | 1 Dec 2015 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Adrian Hayday (Supervisor) & Jonathan Barker (Supervisor) |