ApoE is known to have multiple varied effects on peripheral as well as brain innate immune cells which impact cellular lipid content as well as expression and interaction with other immune-stimulatory molecules. The modulation of innate immune cell function by ApoE obviously impacts those cells directly, but also effects downstream adaptive immune cell activation relevant to translational models of disease. This is poignantly illustrated in two translational disease models in mice: the ApoE knockout/HFD atherosclerosis model and the still emerging hiT sporadic Alzheimer’s disease model. In the former, the absence of ApoE essentially unleashes pathogenic self-reactive CD8 T cells by altering antigen presentation to them by innate immune cells. The pathogenic, self-reactive T cells go on to mediate tissue damage by lytic targeting of tissue cells and promotion of inflammation, resulting in a tissue-specific pathology of arteries, atherosclerosis. In the latter, aberrant age-related lymphocyte expansion results in predominance of self-reactive CD8 T cells that target constitutively MHC I-positive neuronal cells, to result in widespread neuronal loss that is dependent on the lytic protein, Perforin, and to a lesser extent the proinflammatory cytokine, IFNγ. CD4 T cells are involved in each disease model, but are neither necessary nor sufficient for their induction. Both models have led to successful predictions in their human disease counterparts, and in the case of atherosclerosis has helped verify it as a bona fide T cell autoimmune disorder. The effects of ApoE variant isoforms on immune activity in both of these disease models, suggest that its predominant impact on clinical disease may be in suppressing the emergence of pathogenic, self-reactive T cells to greater or lesser extent. In this respect, the involvement of ApoE variants in human disease could represent a biomarker for the involvement of T cell autoimmunity, and a guidepost for considering T cell immunotherapies.