Temkin, Mia; (2025) Immune recognition of fungal viability. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neutrophils are key effector cells of the innate immune system. This study highlighted multiple ways in which neutrophils deploy PD-L1 in response to fungal infections. Neutrophils upregulate PD-L1 on their membrane in response to fungal infections. They can accumulate PD-L1 on actin cuffs in response to live or dead hyphae. Most notably, in response to dead hyphae, they can deposit PDL1 on the hyphae. Both these mechanisms occur in vitro and in vivo. PD-L1, a key immune checkpoint molecule, dampens the immune response by binding to its receptor, PD-1. Recent studies have shown that PD-L1 on neutrophils plays a key role in the immune response to fungal infections. Infections from Candida albicans and Aspergillus fumigatus are deadly in immunocompromised individuals. Neutrophils upregulate PD-L1 in response to fungal infections, and the PD-1/PD-L1 pathway has been shown to have therapeutic potential for fungal infections. Actin cuffs are dynamic and neutrophils form them as they attack the hyphae. Accumulation of PD-L1 on the actin cuff is dependent on actin cuff formation. Since actin cuffs are formed both on live and dead hyphae, this is a viabilityindependent mechanism. This work also shows that neutrophils can mark specifically dead hyphae by depositing PD-L1, independent of actin cuff formation. This PD-L1 deposition is dependent on ROS and MPO activity, and my data suggests it is due to cleavage of PD-L1 by matrix-metalloproteinases. Finally, microbe-associated PD-L1 was shown to inhibit macrophage activation in vitro. In vivo data suggests that neutrophil-derived PD-L1 plays a larger role in debris clearance than pathogen control and is detrimental to effective debris clearance. Microscopy of lung tissue showed that mice which lacked PD-L1+ neutrophils resolved acute infections faster with lower pathology, compared to mice which had PD-L1+ neutrophils. Further, PD-L1 on neutrophils affected macrophage polarisation and fungal debris clearance after infection, with mice which lacked PD-L1+ neutrophils clearing fungal debris faster and having more M2-like macrophages post-infection. These data present a novel mechanism through which neutrophils can regulate other immune cells and the immune environment based on fungal viability. These results point to possible therapeutic targets for fungal infections, cancer, and autoimmune diseases.

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