Identification of a PRDM1-regulated T cell network to regulate T cell driving plaque inflammation in human and mouse atherosclerosis

Abstract

Abstract T cells have a prominent role in the pathogenesis of atherosclerosis, although their exact function remains elusive. Here, we pursued a network-driven approach to identify T cell-associated gene programs driving the transition from low- to high-risk human plaques. In this study 43 human carotid arterial plaques were collected and stratified based on absence (low-risk) or presence (high-risk) of intraplaque haemorrhage (IPH). Lesion RNA was subjected to microarray gene expression analysis and analysed by Weighted Gene Co-expression Network Analysis (WGCNA). We identified a co-expressed gene cluster displaying a strong T cell signalling signature in high- versus low-risk plaque, which was tightly connected to subnetworks of angiogenesis and interferon-signalling. WGCNA-based Bayesian network inference, cell-type deconvolution and single-cell gene expression revealed that this T cell-associated gene program was likely linked to effector-memory cytotoxic CD8+ T cells, underpinning the central role of T cells in plaque destabilization. Gene regulatory analysis identified cytotoxic T cell-related transcription factors, like PRDM1, regulating this plaque T cell gene program. Moreover, we demonstrated in LDL receptor knockout mice with T cell-specific Prdm1 deficiency, that lack of Prdm1 in T cells resulted in larger, more advanced plaques. In conclusion, our study reveals a PRDM1-regulated T cell footprint in high- versus low-risk human atherosclerotic lesions and murine atherosclerotic plaque development, thereby identifying this network as a potential target for intervention in adverse T cell responses. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The European Research Area Network on Cardiovascular Diseases (ERA-CVD and Dutch Heart Foundation)