Zymosan by-passes the requirement for pulmonary antigen encounter in lung tissue-resident memory CD8+ T cell development

Abstract

Tissue-resident memory T cells (Trm) in the lung provide a frontline defence against respiratory pathogens. Vaccination models that lodge CD8 + Trm populations in the lung have been developed, all of which incorporate the local delivery of antigen plus adjuvant into the airways; a necessary approach as local cognate antigen recognition is required for optimal lung Trm development. Although pulmonary delivery of antigen is important for lung Trm development, the impact the co-administered adjuvant has on Trm differentiation is unclear. We show that while altering the adjuvant co-administered with the pulmonary delivered antigen does not impact the size of the lung Trm population, a particular adjuvant, zymosan, when administered into the airways without antigen can drive effector CD8 + T cells to differentiate into lung Trm. Zymosan signalling via dectin-1 receptor was sufficient to promote antigen-independent lung Trm development. When combined with an injectable influenza vaccination regime, intranasal zymosan delivery significantly boosted the size of the influenza virus-specific lung Trm population. Our results highlight that eliciting the appropriate local inflammatory milieu can by-pass the requirement for local antigen recognition in lung Trm development and emphasises that the appropriate selection of adjuvant can greatly improve vaccines that aim to elicit pulmonary Trm.Mucosal Immunology (2019) 12:403-412; https://doi.

Bystander Activation of Pulmonary Trm Cells Attenuates the Severity of Bacterial Pneumonia by Enhancing Neutrophil Recruitment

“…While both cohorts of mice developed equivalent circulating memory OT-I cells and had equal-sized populations of total OT-I memory CD8 + T cells in the lung, only the cohort administered the OVA protein developed CD103 + CD69 + OT-I Trm cells, which are known to exclusively localize to the lung parenchyma (Pizzolla et al, 2017) (Figures 4D and 4E). This is consistent with prior studies demonstrating that lung Trm cell development is largely dependent on local cognate antigen recognition and influenced by the choice of adjuvant (Caminschi et al, 2019;Wakim et al, 2015). To determine whether bystander-activated lung Trm cells were specifically responsible for boosting lung neutrophil recruitment, we intranasally delivered into the airways of mice 10 8 colony-forming units (CFUs) of viable S. aureus and 3 h later quantitated neutrophil numbers in the lungs.…”

“…injection and intranasally received 1 mg of LPS with or without 300 mg of Ovalbumin (Sigma) in a volume of 30 ml. The method for in vitro activation of CD8 + T cells has previously been described (Caminschi et al, 2019).…”

Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8+ T cells

“…These data are in contrast to a study showing that circulating T EM cells were able to re-seed the lung T RM cell pool 16 . The observation that lung T RM cells could develop independently of pulmonary antigen encounter under specific inflammatory conditions may explain this discrepancy 38 . Thus, there may be scenarios where circulating T EM cells can convert into lung T RM cells, but further investigation is required to define these antigen-independent mechanisms.…”

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

“…It is possible that regulatory Trm cells, which are typically not associated with host resistance to fungal infection, dampen the protective effects of Th17 cells (de Araujo et al, 2017;Galdino et al, 2018). It has been shown, that zymosan (predominantly composed of β1,3 glucan) can induce anti-inflammatory effects on T cell differentiation and promote the generation of regulatory T cells (Caminschi et al, 2019;Dillon et al, 2006). Thus, the capacity of intranasally delivered β-glucan to promote lung regulatory Trm may have contributed the failure to induce protection.…”