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Title: The role of intraepithelial lymphocytes and type 2 immunity for tissue homeostasis and carcinogenesis in the skin
Author: D'Alessandri, Timothy
ISNI:       0000 0004 6496 0852
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The skin is under constant renewal whilst frequently being exposed to challenges such as physiochemical disruption and ultraviolet-radiation. How homeostatic control is maintained in the tissue alongside protective mechanisms is poorly understood. Among the basal epithelial cells (EC) is a population of resident intraepithelial lymphocytes (IEL), which provide host-protective immune surveillance (IS). The mouse epidermis is home to a particular IEL termed the dendritic epidermal T cell (DETC). The induction and functions of IS and type 2 immunity at body barrier surfaces remains enigmatic. The aim of this thesis is to investigate the mechanism(s) by which DETC provide IS and maintain epidermal homeostasis. I show that DETC communicate with EC via cytokine IL13. Skin EC are activated by DETC-derived IL13, which enables a canonical EC stress response to various topical challenges. In the absence of IL13, or canonical DETC, the skin is significantly impaired with decreased ability to restore its barrier after insult and increased susceptibility to cutaneous carcinogenesis. Mechanistically, IL13 affected the rate of EC movement through the epidermis, which may explain its importance for epidermal integrity and its suppressive effect on skin carcinogenesis. These findings demonstrate that IL13 acts as a molecular bridge between DETC and EC, and that this interaction provides an integrated local tissue response to perturbation of homeostasis. Finally, I also observed that mice lacking canonical DETC had a reduced ability to repair EC DNA damage following acute carcinogen insult; revealing a hitherto unappreciated aspect of IS. These data support a critical host-defensive role particularly of type 2 immunity in regulating EC tissue homeostasis in multiple settings. Given the considerable and increasing burden of allergic and malignant disease, these data are highly germane to human medicine, and also contribute healthily to the exciting, nascent field studying allergy-cancer interactions; allergooncology.
Supervisor: Strid, Jessica ; Botto, Marina Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral