Abstract Body (Do not enter title and authors here): Background: The apoB-100 peptide P210 is an atherosclerosis-related antigen. P210 conjugated-nanoparticles (P210-PAM) are internalized by antigen-presenting cells to elicit T cell responses and reduce atherosclerosis in mice. However, if and how P210 modulates human T cell responses is not known. We investigated the intrinsic T cell response to P210 in both healthy and atherosclerotic cardiovascular disease (ASCVD) subjects. Methods: We evaluated the T cell response to unconjugated P210 or P210-PAM in PBMCs of healthy subjects (N=15) and stable ASCVD patients (N=27) using the Activation Induced Marker (AIM) assay, where a change of 1.5-fold relative to unstimulated cells is considered the activation threshold and a value of 1 considered no response. Under IRB approval, PBMCs from stable ASCVD patients were collected within 1 year of acute MI or stroke, or a diagnosis of peripheral artery disease (PAD). To investigate effects on innate cells, monocytes from healthy subjects were phenotyped by flow cytometry staining after stimulation with P210-PAM. Results: P210 significantly increased CD4+CD69+CD154+ T cells in healthy subjects compared to ASCVD patients (2.2±1.9 vs 0.8±0.6 fold-change; P=0.01) without affecting other T cell activation markers. In healthy subjects, CD4+CD69+CD154+ T cell response to P210-PAM stimulation was similar compared to P210 stimulation (1.5±0.7 vs 2.2±1.9 fold-change) but was significantly increased in ASCVD patients (1.8±1.8 vs 0.8±0.7 fold-change, respectively; P=0.02). CD4+CD134+CD137+ T cells were also significantly increased by P210-PAM compared to P210 in ASCVD patients (2.8±2.0 vs 1.9±1.8 fold-change; P<0.01) but not in control subjects. Monocyte-enriched PBMCs of healthy subjects (N=13) stimulated with P210-PAM significantly increased CD64+CD80+ cells (32.3±11.9% vs 3.1±2.8%; P<0.001), CD11b+CD209+ cells (3.7±2.2% vs 2.0±1.6%; P<0.01), CD14+CD16+ cells (13.9± 9.5% vs 0.9±0.8%; P<0.001) and CD14-CD16+ cells (37.3±18.7% vs 0.9±1.1%; P<0.001), with significantly reduced CD14+CD16- cells (16.9±14.6% vs 60.0±21.0%; P<0.001). Conclusions: CD4+ T cell response to P210 is impaired and can be rescued by P210-PAM in stable ASCVD patients. Such rescue may be mediated by P210-PAM provoking a shift in monocytes from classic inflammatory to non-classic anti-inflammatory phenotype. Our results support the dynamic existence of T cell response to P210 and the development of P210-PAM as potential immune-modulator therapy for human ASCVD.