Macrophage-derived foam cells are a defining feature of atherosclerotic lesions. Vulnerable plaques contain more foam cells and larger necrotic cores. However, when foam cells are generated in vitro (Cho,H. et al. Physiological Genomics 29:149-160, 2007) or in mice (Spann,N.J. et al., Cell. 151:138-152, 2012), their overall phenotype is anti-inflammatory, not pro-inflammatory. Yet, in atherosclerotic lesions foam cells show a pro-inflammatory phenotype, based on phenotyping by immunofluorescence and other methods. This apparent discrepancy suggests that an additional factor not present in reductionist systems drives foam cell inflammation. We propose that this additional factor are CD4 T cells that provide pro-inflammatory cytokines including IFN-γ, IL-17 and TNF-α. Multiphoton microscopy of Apoe-/- mouse aortas show that CD11cYFP antigen-presenting cells become rounded and less motile, consistent with conversion to foam cells. We show that adoptive transfer of antigen-experienced CD44hiCD62L- CD4 T cells induces production of IFN-γ, IL-17 and TNF-α. IFN-γ is very efficient at increasing uptake of oxidized low density lipoprotein (oxLDL) in macrophages in culture. Our experiments suggest that both antigen-experienced T cells and a suspected autoantigen are present in Apoe-/- mice. These data also suggest that modulating the autoimmune response might be effective in preventing or treating atherosclerosis.