BACKGROUND: Inflammation is a key driver of atherosclerosis, yet the mechanisms sustaining inflammation in human plaques remain poorly understood. This study uses a network-based approach to identify immune gene programs involved in the transition from low- to high-risk (rupture-prone) human atherosclerotic plaques. METHODS: Expression data from human carotid artery plaques, both stable (low-risk, n = 16) and unstable (high-risk, n = 27), were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA). Bayesian network inference, operated on the eigengene values from the WGCNA, further extended the WGCNA analysis, and similarity to the signature of T cell subsets was validated in single-cell RNA sequencing data of human plaques, and a loss-of-function study in a mouse model of atherosclerosis. In silico drug repurposing was performed to identify potential therapeutic targets. RESULTS: Our analysis revealed a distinct gene module with a prominent T cell signature, particularly in unstable plaques. Key regulatory factors, RUNX3, IRF7 and in particular PRDM1, were significantly downregulated in plaque T cells from symptomatic versus asymptomatic patients, indicating a protective role. Additionally, as PRDM1 is downstream of IRF7, we opted for PRDM1 as a key target. T cell-specific Prdm1 deficiency in Western-type diet fed Ldlr knockout mice featured accelerated plaque progression. Finally, as PRDM1 targeting drugs are not yet available, we performed in silico drug repurposing, identifying EGFR inhibitors as promising therapeutic candidates. CONCLUSIONS: This study highlights a PRDM1-regulated T cell network that distinguishes high-risk from low-risk plaques and demonstrates the regulatory role of T cell PRDM1 in controlling atherosclerosis, positioning this pathway as a promising therapeutic target.