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The role of innate and adaptive IL-17 producing cells in chemical allergy
[Thesis]. Manchester, UK: The University of Manchester; 2013.
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Abstract
The Interleukin (IL)-17 cytokine family, expressed by T helper (Th)17 cells and γδ T cells, plays pivotal roles in adaptive immune responses. They have been implicated in autoimmune and allergic diseases as well having roles in bacterial and fungal clearance. Importantly, IL-17 producing γδ T cells have been shown to be critical for the development of adaptive Th17 responses in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis. Interestingly, natural ligands of the aryl hydrocarbon receptor (AhR) are known to influence the development of Th17 cells. It has been shown previously that prolonged topical exposure of mice to the contact allergen 2-4 dinitrochlorobenzene (DNCB) or to the respiratory sensitiser trimellitic anhydride (TMA) causes the preferential development of a preferential T helper (Th)1 or Th2 response, respectively. The presence of the novel IL-17 family cytokines and their cellular source was investigated following both single and prolonged exposure to allergen.Exposure only to the contact allergen DNCB resulted in up-regulation of the expression of IL-17 by dermal γδ T cells. It was shown also that topical application of a range of contact allergens and of the respiratory allergen TMA resulted in IL-17 expression by γδ T cells in the lymph node draining the site of exposure. However, differential kinetics were observed between the two classes of allergens. Exposure to the contact allergens resulted in rapid expression of IL-17 within 6-16 h, whereas the respiratory allergen displayed considerably delayed kinetics, with maximal levels detected 48 h post exposure. Treatment with DNCB only was shown to be associated with the development of Th17 cells following prolonged exposure to chemical allergen. Thus DNCB provoked a Tc1/Th1/Th17 profile, in contrast prolonged exposure to TMA resulted in a very selective Th2 cytokine pattern. The influence of γδ T cells on polarised responses to chemical allergens was investigated also using γδ T cell knockout mice; here the adaptive Th17 response induced by DNCB was completely abrogated. These data demonstrate that the absence of IL-17 production by γδ T cells during the early innate immune response affects the subsequent adaptive Th17 response stimulated by chemical contact allergens.Finally, the importance of the affinity of the AhR for endogenous ligands during in vitro Th17 polarisation was assessed. Using three strains of mice with differential AhR affinities the contribution of ligation of these receptors in Th17 cell development was investigated. In all three strains AhR ligation was required for optimal polarisation of Th17 cells, even in strains that are reported to express a low affinity receptor. These data suggest that across a range of receptor affinities, including low affinity receptors analogous to that of humans, endogenous AhR ligands may play a major role in driving Th17 cell differentiation, regardless of receptor phenotype.