IRF8 Drives Conventional Type 1 Dendritic Cell Differentiation and CD8+ T Cell Activation to Aggravate Abdominal Aortic Aneurysm Development

Abstract

Abdominal aortic aneurysm (AAA) is the most common true aneurysm worldwide, and recent studies suggest that dendritic cells (DCs) play a key role in its development, though the specific subtypes and underlying mechanisms remain unclear. In this study, the role of interferon regulatory factor 8 (IRF8) in AAA is investigated by focusing on its effect on the differentiation of DC precursors into conventional type 1 dendritic cells (cDC1s). It is found significant infiltration of HLA-DR⁺ IRF8⁺ cells in human AAA tissue samples. In mice, DC-specific overexpression of Irf8 exacerbates aneurysm expansion following periadventitial elastase application, while DC-specific Irf8 deletion attenuates AAA development. Batf3^−/− mice, which lack cDC1s, exhibit AAA characteristics similar to the Irf8-deleted mice. Additionally, an increased population of activated CD8⁺ T cells is observed in the DC-Irf8 overexpressed mice, while the DC-Irf8 deletion mice show a decrease in these cells. Blocking antigen cross-presentation to CD8⁺ T cells also reduces AAA progression. Tissue microarray analysis of human aortic samples further confirms a correlation between IRF8 expression and AAA development. These findings suggest that IRF8 activation promotes cDC1 differentiation, leading to the recruitment of CD8⁺ T cells, which contribute to aortic wall destruction and AAA formation.