T cells in cardiovascular disease Dyslipidemia and checkpoints

Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Together with hyperlipidemia, aberrant T cell activation and the resulting inflammation, is a major contributing factor in the progression of including atherosclerosis. Additionally, inhibition of pro-inflammatory cytokines and the blockage of activating immune checkpoints lowers the risk of major adverse cardiac events without an effect on blood lipids. In this thesis we explore the effects of hyperlipidemia on T cells. In the first part, we looked at the effect of lipids on T cells. We found that hyperlipidemia causes an inflammatory response on T cells through VLDL derived lipids. Specifically, CD4+ T cells were responsive towards VLDL and took the particles up though CD36. Furthermore, mice that lack regulatory T cell CD36 are protected against atherosclerosis. This result further underpins an important role for these lipoproteins. In the second part of this thesis, we focused on immune checkpoints expressed by T cells. We found that CD40L activation results in cell proliferation and increased inflammation that was mediated through its newly identified binding partner, RACK1. Activation of CD40L’s binding partner CD40 reduces CD4 T cell activation and increases CD8 T cell activation. Interestingly enough no effect on atherosclerosis was observed. CBL-b is an inhibitory protein that integrates signals from difference stimuli, including from the immune checkpoint CD28. Removing this from protein from T cells reduces plaque size but increases plaque T cell infiltration.