Visceral Pleural Macrophages regulate lung immunity during homeostatic and pathological conditions

Abstract

Macrophages are pivotal in maintaining pulmonary health due to their multifaceted roles in immune surveillance, tissue homeostasis, and response to injury. Therefore, exploring the heterogeneity of lung macrophages is paramount to unravelling their intricate functions in lung physiology and pathogenesis. In this thesis, using a novel murine binary transgenic ‘splitCre’ model capitalising on the overlapping promoter activities of the Cx3cr1 and Lyve1 genes, a distinct population of macrophages residing specifically in the visceral pleura of the lung has been identified, which were termed visceral pleura macrophages (VPM). VPM exhibit a unique gene expression profile distinct from other pulmonary macrophage subsets, indicating potential specialised functions tailored to their anatomical niche. Moreover, VPM express cell-surface MHCII molecules, suggesting communication with CD4+ T cells and, hence, immune modulation within the lung microenvironment. To directly test this antigen presentation function of this macrophage population, targeted ablation of MHCII on VPM was performed. Mice with MHCII-deficient VPM (mutants) resulted in a significant reduction of lung-resident CD4+ Foxp3+ T regulatory cells (Tregs), which are pivotal in immune tolerance and regulation. Specifically, a reduction of tissue-resident Tregs expressing ST2 (tisTreg ST2) was observed in the lungs of the mutants relative to the control. Treg impairment was associated with an accumulation of activated CD8+ T cells in the lung of aging mutant mice, indicative of altered immune homeostasis. Importantly, the disrupted VPM-Treg communication was shown to be impinged on the course of pulmonary protective immunity. Thus, influenza-infected mice showed impaired resolution and changes in their corresponding immune cell composition. In conclusion, this thesis sheds light on the previously unrecognised role of a unique pulmonary macrophage population, the VPM, in orchestrating immune homeostasis and protective responses within the lung, particularly in the context of infectious diseases. The in-depth characterisation of VPM and their crosstalk with T cell populations might open new avenues for modulating pulmonary immunity.

Date of Award	8 Oct 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Tracy Hussell (Supervisor)