Roshni Roy Chowdhury1,2, Jessica D'Addabbo3, Xianxi Huang4, Stefan Veizades3,5,6,7, Koki Sasagawa3, David M Louis8, Paul Cheng3,5, Jan Sokol3,5, Annie Jensen3,5,8, Alexandria Tso3,5,8, Vishnu Shankar8, Ben Shogo Wendel8, Isaac Bakerman3,5, Grace Liang3,5, Tiffany Koyano9, Robyn Fong9, Allison N Nau8, Herra Ahmad10, Jayakrishnan Gopakumar10, Robert Wirka11, Andrew S Lee12, Jack Boyd9, Y Joseph Woo9, Thomas Quertermous3,5, Gunsagar Singh Gulati13, Siddhartha Jaiswal10, Yueh-Hsiu Chien1, Charles Kwok Fai Chan5,13, Mark M Davis1,8,14, Patricia K Nguyen3,5,8. 1. Department of Microbiology and Immunology (R.R.C., Y.-H.C., M.M.D.), Stanford University, Stanford, CA, USA. 2. CA, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago' IL (R.R.C.). 3. Department of Medicine, Cardiovascular Medicine (J.D., S.V., K.S., P.C., J.S., A.J., A.T., I.B., G.L., T.Q., P.K.N.), Stanford University, Stanford, CA, USA. 4. Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Guangdong, China (X.H.). 5. Stanford Cardiovascular Institute (S.V., P.C., J.S., A.J., A.T., I.B., G.L., T.Q., C.K.F.C., P.K.N.), Stanford University, Stanford, CA, USA. 6. Edinburgh Medical School, United Kingdom (S.V.). 7. Centre for Inflammation Research, University of Edinburgh, Scotland (S.V.). 8. Institute for Immunity, Transplantation and Infection (D.M.L., A.J., A.T., V.S., B.S.W., A.N.N., P.K.N., M.M.D.), Stanford University, Stanford, CA, USA. 9. Department of Cardiothoracic Surgery (T.K., R.F., J.B., Y.J.W.), Stanford University, Stanford, CA, USA. 10. Department of Pathology (H.A., J.G., S.J.), Stanford University, Stanford, CA, USA. 11. Department of Medicine and Cell Biology and Physiology, and McAllister Heart Institute, University of North Carolina-Chapel Hill, NC (R.W.). 12. Institute for Cancer Research, Shenzhen Bay Labs, China (A.S.L.). 13. Institute for Stem Cell Biology and Regenerative Medicine (G.S.G., C.C.), Stanford University, Stanford, CA, USA. 14. Howard Hughes Medical Institute (M.M.D.), Stanford University, Stanford, CA, USA.
Abstract
BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4<CD8), exhibiting clonal expansion of specific TCRs. Interestingly, we found that these plaque T cells had TCRs specific for influenza, coronavirus, and other viral epitopes, which share sequence homologies to proteins found on smooth muscle cells and endothelial cells, suggesting potential autoimmune-mediated T-cell activation in the absence of active infection. To better understand the potential function of these activated plaque T cells, we then interrogated their transcriptome at the single-cell level. Of the 3 T-cell phenotypic clusters with the highest expression of the activation marker HLA-DRA, 2 clusters expressed a proinflammatory and cytolytic signature characteristic of CD8 cells, while the other expressed AREG (amphiregulin), which promotes smooth muscle cell proliferation and fibrosis, and, thus, contributes to plaque progression. CONCLUSIONS: Taken together, these findings demonstrate that plaque T cells are clonally expanded potentially by antigen engagement, are potentially reactive to self-epitopes, and may interact with smooth muscle cells and macrophages in the plaque microenvironment.
BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4<CD8), exhibiting clonal expansion of specific TCRs. Interestingly, we found that these plaque T cells had TCRs specific for influenza, coronavirus, and other viral epitopes, which share sequence homologies to proteins found on smooth muscle cells and endothelial cells, suggesting potential autoimmune-mediated T-cell activation in the absence of active infection. To better understand the potential function of these activated plaque T cells, we then interrogated their transcriptome at the single-cell level. Of the 3 T-cell phenotypic clusters with the highest expression of the activation marker HLA-DRA, 2 clusters expressed a proinflammatory and cytolytic signature characteristic of CD8 cells, while the other expressed AREG (amphiregulin), which promotes smooth muscle cell proliferation and fibrosis, and, thus, contributes to plaque progression. CONCLUSIONS: Taken together, these findings demonstrate that plaque T cells are clonally expanded potentially by antigen engagement, are potentially reactive to self-epitopes, and may interact with smooth muscle cells and macrophages in the plaque microenvironment.
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