Allergic diseases and parasitic infections, such as asthma and schistosomiasis, are characterised by type-2 inflammation. It is understood that dendritic cells (DCs) are critical to drive type-2 inflammatory responses in allergic and helminthic diseases, via induction of T helper 2 (Th2) cells. In addition to inflammatory responses, regulatory responses arise during allergic airway inflammation (AAI), with dampening of inflammation by T regulatory cells (Tregs) critical. DCs have been shown to promote Treg expansion. However, the interaction between DCs and Tregs during ongoing AAI is not well understood, particularly with respect to AAI driven by fungal allergens. In this thesis we begin by elucidating Treg responses during fungal, Aspergillus fumigatus (A.f.) driven AAI, revealing an expansion of pulmonary Tregs alongside the development of the inflammatory response. We go on to show that Tregs specifically expand at the site of AAI, whilst increasing their expression of the suppressive cytokine IL-10. Previous reports have shown Tregs to be unstable during inflammation, gaining an inflammatory phenotype or losing expression of the characteristic transcription factor Foxp3. During A.f. driven AAI we found Tregs to be stable, however a small proportion of these cells began to express the Th2 associated cytokine IL 4. By sorting and performing in vitro suppression assays on Tregs from control or A.f. driven AAI we found that IL-4 expressing Tregs had reduced suppressive capacity. We next moved on to ask how Treg expansion was controlled during A.f. driven AAI, focusing on the role of DCs due to their published importance in this role. By systematically depleting DC subsets we reveal that type-2 conventional DCs (cDC2s) that express the lectin MGL2 are required for expansion of Tregs during A.f. driven AAI. In addition, we reveal DC expression of the integrin avb8, critical for activating the suppressive cytokine TGF-beta, is also required for lung Treg expansion. Moving on from AAI, we go on to investigate the regulation of pulmonary type-2 immune responses in parasite infection, focusing on the trematode Schistosoma mansoni (S. mansoni). We provide novel insights into lung immunological responses to S. mansoni at both lung migratory and adult, egg producing (patent) stages of its life cycle in both a mouse model and during human infection. During murine pulmonary schistosomiasis we reveal type-2 dominated inflammatory responses at both lung migratory and patent stages of infection, in addition to an expansion of cDC2s. Utilising sputum as a proxy for lung responses in human S. mansoni infection we observe trends for an increase in inflammatory cytokines during lung migratory infection, which are not observed in endemic patent S. mansoni infection. With the exception of an increase in Th cells during endemic patent S. mansoni infection, there were no significant changes in sputum granulocytes or lymphocytes measured. In line with our murine studies, we reveal consistent increases in cDCs, and in particular cDC2s during human lung migratory and endemic patent infection. Going back to the murine model, we reveal cDC2s to contribute to driving type-2 inflammatory responses to S. mansoni infection. Taken together this work provides novel insights into the regulation of pulmonary type-2 inflammation, centring on the role of cDC2s in promoting both Th2 and Treg responses.
|Date of Award||1 Aug 2021|
- The University of Manchester
|Supervisor||Peter Cook (Supervisor) & Andrew MacDonald (Supervisor)|
- T cell
- dendritic cell