The phenotype and function of nasal mucosal T cells in health and polyposis

• Main Author: Lam, Emily Puo San
• Other Authors: Lavender, Paul
• Published: King's College London (University of London) 2015
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677097

Chronic rhinosinusitis with nasal polyposis (CRSwNP) in western countries is characterised by eosinophilia and IgE production. Type 2 innate lymphoid cells from polyps produce Th2 cytokines in response to IL-25 and IL-33 but the relevance of this axis to local mucosal T cell responses is unknown. Furthermore, the local T cell response in relation to the healthy versus inflamed nasal mucosa remains poorly characterised. In this thesis, the nasal mucosal T cell phenotype in health and CRSwNP and the role of the IL-25/IL-33 axis in the adaptive Th2 response was examined. Normal nasal mucosal and nasal polyp tissues were cultured in a short-term explant model before analysis. Peripheral blood from the same subjects were analysed in parallel to determine the local versus peripheral response. Polyp-derived cells contained a discrete population of IL-25 receptor (IL-25R) positive Th2 cells, which were absent in the periphery and healthy nasal mucosa. IL-25R+CD4+ polyp Th2 cells co-expressed ST2 and responded to IL-25 and IL-33 with enhanced IL- 5 and IL-13 production. Within the IL-25R+CD4+ population, several identical TCR Vβ complementarity-determining region 3 (CDR3) sequences were detected in different subjects, suggestive of clonal expansion driven by common antigen(s). Th17 cells were abundant in healthy nasal and polyp explants but not in the periphery and represented the most preferentially expressed T cell subset in the nasal mucosa compared to the periphery. Furthermore, this was associated with a protective signature. This study is the first demonstration of human IL-25R+ Th2 cells co-expressing ST2. IL-25 and IL-33 may interact locally with IL-25R+ST2+ polyp T cells to augment Th2 responses in CRSwNP. Targeting the IL-25/IL-25R and IL-33/ST2 pathways may represent attractive therapeutic strategies. The strong Th17 signature in the normal nasal mucosa suggests Th17 may be present in a protective, rather than pathogenic, capacity for normal nasal mucosal immunity.