{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:04Z","timestamp":1787028484582,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Uehara Memorial Foundation","award":["NIH HL P01 HL136275"],"award-info":[{"award-number":["NIH HL P01 HL136275"]}]},{"name":"Uehara Memorial Foundation","award":["R35 HL145241"],"award-info":[{"award-number":["R35 HL145241"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the decades-old knowledge that males and people with diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD), the reasons for this association are only partially understood. Among the immune cells involved, recent evidence supports a critical role of T cells as drivers and modifiers of CAD. CD4+ T cells are commonly found in atherosclerotic plaques. We aimed to understand the relationship of CAD with sex and DM by single-cell RNA (scRNA-Seq) and antibody sequencing (CITE-Seq) of CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by scRNA-Seq combined with 49 surface markers (CITE-Seq). CAD severity was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD\u2212. Four pairs of groups were matched for clinical and demographic parameters. To test how sex and DM changed cell proportions and gene expression, we compared matched groups of men and women, as well as diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 16 women and 45 men with and without coronary artery disease and with and without DM. We identified 16 clusters in CD4+ T cells. The proportion of cells in CD4+ effector memory cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. This same cluster, CD4T8, was significantly decreased in female participants, along with two other CD4+ T cell clusters. In CD4+ T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. We conclude that (1) CAD and DM are clearly reflected in PBMC transcriptomes, and (2) significant differences exist between women and men and (3) between subjects with DM and non-DM.<\/jats:p>","DOI":"10.3390\/ijms23179875","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T00:13:56Z","timestamp":1661904836000},"page":"9875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Sex Differences in Coronary Artery Disease and Diabetes Revealed by scRNA-Seq and CITE-Seq of Human CD4+ T Cells"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1640-6182","authenticated-orcid":false,"given":"Ryosuke","family":"Saigusa","sequence":"first","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenifer","family":"Vallejo","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishab","family":"Gulati","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujit Silas Armstrong","family":"Suthahar","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1497-7480","authenticated-orcid":false,"given":"Vasantika","family":"Suryawanshi","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7888-5019","authenticated-orcid":false,"given":"Ahmad","family":"Alimadadi","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Makings","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Durant","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Freuchet","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Drago","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, VA 22904, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Taylor","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, VA 22904, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coleen A.","family":"McNamara","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, VA 22904, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avishai","family":"Shemesh","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA 94143, USA"},{"name":"Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-3952","authenticated-orcid":false,"given":"Lewis L.","family":"Lanier","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA 94143, USA"},{"name":"Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine C.","family":"Hedrick","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"},{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9339-3672","authenticated-orcid":false,"given":"Klaus","family":"Ley","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"},{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Bioengineering, University of California San Diego, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1002\/cphy.c210014","article-title":"Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk","volume":"12","author":"Singh","year":"2021","journal-title":"Compr. 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