Temporal immune reprogramming following ambient particulate exposure identifies a potential trigger pathway for plaque destabilisation

Background

Short-term exposure to particulate air pollution is associated with acute cardiovascular events, yet the proximal human immune responses linking exposure to vascular injury remain poorly defined.

Purpose

To characterise temporally structured immune responses to real-world particulate exposure and assess their relevance to pathways implicated in acute cardiovascular risk.

Methods

We analysed 105 participants undergoing clinically indicated CT coronary angiography in the BioHEART-CT cytometry substudy. A single peripheral blood sample was obtained per participant. Circulating immune phenotypes were quantified using high-dimensional mass cytometry.

Ambient particulate exposure (PM₂.₅ and PM₁₀) was derived from regional air-quality monitoring stations (New South Wales Department of Environment) and linked to each participant by date of presentation. Exposure metrics included same-day and lagged concentrations (0–3 days). Median PM₂.₅ was ~7 µg/m³, consistent with urban background exposure, with higher values reflecting episodic pollution events. Associations were assessed using distributed lag non-linear models adjusted for meteorological covariates.

Results

Particulate exposure was associated with a temporally structured immune response inferred across exposure lags. At early lags (0–1 days), higher exposure was associated with increases in regulatory and antigen-presenting phenotypes, including CCR6⁺ and HLA-DR⁺ regulatory T cells and plasmacytoid dendritic cells. At later lags (2–3 days), there was a shift towards effector activation, characterised by reductions in conventional T cells and increased expression of trafficking and activation markers, including CCR2⁺ CD8⁺ T cells, CXCR3 signalling, Ki-67 proliferation, and delayed NK cell activation.

This phased pattern indicates early immune regulation followed by pro-inflammatory activation. The implicated pathways, CCR2-mediated monocyte recruitment, CXCR3-driven T cell trafficking, and NK cell activation, are central to vascular inflammation, endothelial dysfunction, and plaque destabilisation.

Notably, these responses were observed at particulate concentrations commonly encountered in urban environments with pollution levels below current guideline thresholds.

Conclusion

Short-term variation in ambient particulate exposure is associated with coordinated, lag-dependent immune reprogramming characterised by early regulatory responses followed by delayed effector activation. Although based on cross-sectional sampling, the temporal structure supports a biologically plausible sequence linking environmental exposure to pathways implicated in plaque destabilisation. These findings provide a translational framework connecting real-world pollution exposure to human immune responses and highlight a potential window for preventive intervention prior to effector activation.

Figure 1. Lag-specific immune responses to particulate exposure.