Ana Hurtado

Introduction.  Atherosclerosis is an inflammatory disease of arterial walls that involves the activation of CD4+ T cells. These proinflammatory T cells then contribute to the inflammatory state secreting cytokines that result in increased lipid accumulation and intimal thickening. CD4+ T cells are therefore an important contributor to atherosclerotic cardiovascular disease that results in heart attacks, stroke and peripheral arterial disease. 1 in 4 deaths in America each year are due to heart disease.¹ Regulatory T cells (T regs) are a population of T cells that help to balance the inflammatory process. Studies have demonstrated that Tregs play a critical role in the progression of atherosclerosis by attenuating the negative effects of CD4+ T cells.^2-3 This could suggest that a pharmacological method to increase the differentiation of naïve T cells into Tregs could prove to be beneficial in the treatment of atherosclerosis.^2-5 Methods. Carotid plaque specimens of patients undergoing endarterectomy of elastic arteries were analyzed; they were classified as stable or unstable and the number of CD4+ T cells were compared to anti-inflammatory Tregs.²  One study sought to investigate the correlation between CD4+ T cells and Tregs in plaque phenotypes using optical coherence tomography (OCT) in acute coronary syndrome patients.³ Another study inhibited an activator of CD4+ T cells in mice called LCK and quantified the various differentiated T cells that accumulated in the atherosclerotic plaques of mice on a high-fat diet.⁴ Results. In the carotid plaque specimens analyzed there were significantly lower numbers of Tregs in unstable lesions compared to the stable ones. This reduction in anti-inflammatory cells during atherogenesis might be an important reason for plaque destabilization.² Acute coronary syndrome patients showed an adaptive immune imbalance toward CD4+ T cells and defective Tregs that predisposed them to atherosclerotic plaque rupture.³ Inhibition of LCK increased Tregs and decreased proinflammatory Th1 T cell numbers.⁴  Conclusion. Studies have found that Treg differentiation and function can attenuate the inflammatory response of atherosclerosis. LCK inhibition can promote the differentiation of Tregs and is a promising therapeutic target. By administering LCK inhibitors as immunomodulatory therapeutic intervention patients with atherosclerosis or at high risk for atherosclerosis because of family history could have reduced arterial wall inflammation and potentially reduced risk of cardiovascular disease complications.

1. Heart Disease Facts. Centers for Disease Control and Prevention. https://www.cdc.gov/heartdisease/facts.htm. Published December 2, 2019. Accessed April 24, 2020.
2. Rohm I, Atiskova Y, Drobnik S, Fritzenwanger M, et al. Decreased regulatory T cells in vulnerable atherosclerotic lesions: imbalance between pro- and anti-inflammatory cells in atherosclerosis. Mediators Inflamm. 2015;2015:364710. doi:10.1155/2015/364710.
3. Ruggio A, Pedicino D, Flego D, et al. Correlation between CD4(+)CD28(null) T lymphocytes, regulatory T cells and plaque rupture: An Optical Coherence Tomography study in Acute Coronary Syndromes. Int J Cardiol. 2019 Feb 1;276:289-292. doi:10.1016/j.ijcard.2018.08.101.
4. Liu J, Guo Z, Zhang Y, et al. LCK inhibitor attenuates atherosclerosis in ApoE(-/-) mice via regulating T cell differentiation and reverse cholesterol transport. J Mol Cell Cardiol. 2020 Feb;139:87-97. doi: 10.1016/j.yjmcc.2020.01.003.
5. Plitas G, Rudensky AY. Regulatory T Cells: Differentiation and Function. Cancer Immunol Res. 2016;4(9):721–725. doi:10.1158/2326-6066.CIR-16-0193