Background <p>Smoking is considered as the major risk factor for the progression of atherosclerosis (AS), whereas the underlying immunological mechanism remains unclear.</p> Methods <p>ApoE^KO mice were treated with cigarette tar via inhalation in vivo, mouse arterial endothelial cells (MAECs) and human coronary artery endothelial cells (HCAECs) were treated with cigarette tar in vitro. Single cell RNA sequencing (scRNA-seq) was utilized to explore the molecular mechanism of CD4⁺ Granzyme A (Gzma⁺) T cells activation in smoke-related atherosclerotic progression.</p> Results <p>Cigarette tar significantly aggravated the development of atherosclerotic lesion in ApoE^KO mice. Results of scRNA-seq and validation experiments further indicated that cigarette tar inhalation significantly increased the proportion of CD4⁺Gzma⁺ T cells, a T cell subset which could lead to endothelial cells (ECs) damage. Concurrently, a significant reduction in the proportion of ECs was observed. Of note, cigarette tar enhanced interaction of ECs and CD4⁺Gzma⁺ T cells via mediating major histocompatibility complex II (MHC II) signaling pathway activation rather than other antigen-presenting cell types. Mechanistically, class II major histocompatibility complex transactivator (CIITA), a key transcriptional regulator of MHC II genes expression, was identified to connect with protein arginine methyltransferases-5 (PRMT5), scoring highest via utilizing mass spectrometry analysis, which triggered symmetrical dimethylation modification of H3R2 and promoted MHC II expression. Meanwhile, CIITA knockout/knockdown, and PRMT5 inhibition/knockdown inhibited the infiltration of CD4⁺Gzma⁺ T cells and MHC II expression of ECs, alleviating the atherosclerotic lesion severity. Additionally, findings from the in vitro co-culture experiment provided additional confirmation that activated CD4⁺Gzma⁺ T cells possessed the capability to induce cytotoxicity in ECs.</p> Conclusions <p>Cigarette tar augments the expression of MHC II in ECs via promoting CIITA nuclear translocation and PRMT5-mediated methylation modification. This process activates CD4⁺Gzma⁺ T cells, which subsequently mediate ECs injury in turn, thereby contributing to the progression of AS. Therefore, CIITA and PRMT5 represent potential therapeutic targets for interventions aimed at mitigating smoke-related AS.</p> Graphical Abstract <p></p>