Background: We have previously reported that the athero-protective effects of immunization of ApoE-/- mice with p210, an apoB-100 peptide, are mediated by CD8+ T cell responses. We have also recently reported that the immune dominance of the p210 epitope in the steady state of naïve mice is altered by p210 immunization. This suggested that the p210-reactive CD8+ T cells have properties of memory T cells. In this study, we investigated the effect of high fat diet on the immunologic niche of p210-reactive CD8+ memory T cells.Methods and Results: Male apoE-/- mice were fed normal chow or high fat diet for 6 weeks. Spleens and bone marrow cells were collected for in-vitro recall stimulation with the p210 peptide. Stimulation with p210 (20ug/ml) for 24 hours did not have a significant effect on CD8+ Effector Memory (EM) or Central Memory (CM) T cells of splenocytes from mice fed normal chow. On the other hand, there was a significant increase in CD8+ EM T cells and a reciprocal reduction in CD8+ CM T cells after p210 stimulation of splenocytes from mice fed a high fat diet. Functional test of CD8+ EM T cells reactive to p210 showed significantly increased degranulation assessed by CD107a stain, suggesting increased cytolytic activity. The pool of p210-reactive memory CD8+T cells in mice fed high fat diet was examined further in the bone marrow. There was a high percentage of CD8+ EM T cells in the bone marrow but was not responsive to p210 stimulation. No effect was observed in the functional profile of bone marrow CD8+ T cells.Conclusion: CD8+ EM T cells reactive to the apoB-100 antigen p210 are found in the spleens of apoE-/- mice fed a high fat diet and have increased cytolytic function after p210 stimulation. Bone marrow CD8+ EM T cells, although present in high percentage, are not reactive to p210. The results suggest that p210-reactive CD8+ T cells may be selective in their immunologic niche in the context of atherosclerosis.