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High-dimensional profiling of peripheral blood mononuclear cells from patients with high-grade CAV versus normal transplant recipients identified IFNG-high CD8+ T cells. CD38+ HLA-DR+ CD8+ effector memory T cells increased in CAV, showed clonal expansion, enhanced IFNG signaling, and stronger cytotoxicity (granzyme B and perforin 1). These cells also infiltrated intimal regions of explanted CAV coronaries, supporting a pathogenic role.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/proinflammatory-and-cytotoxic-cd38-hla-dr-effector-memory-cd8-t-cells-are-peripherally-expanded-in-human-cardiac-allograft-vasculopathy/445929/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/proinflammatory-and-cytotoxic-cd38-hla-dr-effector-memory-cd8-t-cells-are-peripherally-expanded-in-human-cardiac-allograft-vasculopathy/445929.png","ImageObject",300,407,{"name":92,"@type":93},"Connor ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does IFNG play in cardiac allograft vasculopathy after heart transplant?","Question",{"text":112,"@type":113},"IFNG is considered central to the pathogenesis of cardiac allograft vasculopathy, but the peripheral lymphocyte populations involved in the IFNG axis were previously unclear.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which immune cell population was most strongly associated with IFNG in this study?",{"text":117,"@type":113},"Among major immune populations, CD8+ T cells expressed IFNG most highly.",{"name":119,"@type":110,"acceptedAnswer":120},"What did the study find about CD38+ HLA-DR+ effector memory CD8+ T cells in CAV?",{"text":121,"@type":113},"The CD38+ HLA-DR+ CD8+ effector memory CD8+ T cell cluster was significantly increased in CAV, showed clonal expansion, increased IFNG signaling, and enhanced cytotoxicity, and it infiltrated the intima of explanted CAV coronary arteries.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},445929,1790792238,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":41,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},687207022233,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Am J Transplant. Author manuscript; available in PMC 2026 January 07. |\n| --- | --- |\n\nPublished in final edited form as:  \nAm J Transplant. 2026 February ; 26(2): 276–290. doi:10.1016/j.ajt.2025.10.015 .  \nProinflammatory and cytotoxic CD38+ HLA-DR+ effector memory CD8+ T cells are peripherally expanded in human cardiac allograft vasculopathy  \nYuko Tada 1 , Sujit S.A. Suthahar2 , Payel Roy2,3 , Vasantika Suryawanshi2 , Runpei Wu2 , Erpei Wang2 , Felix S. Nettersheim2,4 , Anusha Bellapu3 , Katarzyna Dobaczewska2 , Cheryl Kim2 , Florin Vaida5 , Gerald P. Morris6 , Klaus Ley3 , Paul J. Kim 1,*  \n1 Division of Cardiovascular Medicine, University of California, San Diego, San Diego, California, USA  \n2La Jolla Institute for Immunology, La Jolla, California, USA  \n3 Immunology Center for Georgia, Augusta University, Augusta, Georgia, USA  \n4 Department of Cardiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany  \n5 Department of Family Medicine and Public Health, University of California, San Diego, San Diego, California, USA  \n6 Department of Pathology, University of California, San Diego, San Diego, California, USA  \nAbstract  \nInterferon gamma (IFNG) is thought to play a central role in the pathogenesis of cardiac allograft vasculopathy (CAV) in patients with heart transplant (HTx). However, peripheral lymphocytes participating in the IFNG axis remain largely unknown in human CAV. Using peripheral blood mononuclear cells from International Society for Heart and Lung Transplant grade 2 or 3 CAV (high-grade CAV) and normal patients with HTx, we performed high-dimensional analysis (highgrade CAV, n = 6; normal HTx, n = 12) with cellular indexing of transcriptomes and epitopes using sequencing and variability, diversity, and joining segment sequencing and validated the findings using flow cytometry in an independent cohort (high-grade CAV, n = 11; normal HTx, n = 12) . Among the major immune cell populations, CD8+ T cells expressed IFNG most highly.  \nAmong the CD8+ T cell clusters, the CD38+ HLA-DR+ CD8+ effector memory T cell cluster was significantly increased in CAV compared with normal HTx peripheral blood mononuclear cell samples. This cluster showed clonal expansion, increased IFNG signaling, and enhanced cytotoxicity with granzyme B and perforin 1 overexpression. CD38+ HLA-DR+ CD8+ T cells also infiltrated the intima of explanted CAV coronary arteries. Thus, we concluded that circulating  \nThis is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).  \n*Corresponding author. 9452 Medical Center Drive, MC 7411, La Jolla, CA 92037, [USA. pjk017@health.ucsd.edu](USA. pjk017@health.ucsd.edu) (P.J. Kim) . Declaration of competing interest  \nThe authors of this manuscript have conflicts of interest to disclose as described by American Journal of Transplantation. P.J. Kim reports working at an institution that received research payments from CareDx and Natera. Neither CareDx nor Natera was involved in the conceptualization of the study, data collection and analysis, manuscript preparation, and editing of the final manuscript.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nTada et al. Page 2  \nCD38+ HLA-DR+ CD8+ effector memory T cells may contribute to the pathogenic IFNG axis inhuman CAV.  \nKeywords  \nheart transplant; cardiac allograft vasculopathy; CD8+ T cells  \n1. Introduction  \nCardiac allograft vasculopathy (CAV) limits adult heart transplant (HTx) recipients’longevity to a median survival of 12 years after HTx.1 However, the immune cells that are key to the pathogenesis of human CAV remain undetermined. Consequently, treatment of CAV in patients is limited using contemporary immunosuppressive regimens.2  \nCAV is considered to be mediated by ch","cbCaihdDrzifXeJP","https://ap.wps.com/l/cbCaihdDrzifXeJP","pdf",2870935,"English","# Abstract\n# Keywords\n# 1. Introduction\n# 2. Materials and Methods","[{\"question\":\"What role does IFNG play in cardiac allograft vasculopathy after heart transplant?\",\"answer\":\"IFNG is considered central to the pathogenesis of cardiac allograft vasculopathy, but the peripheral lymphocyte populations involved in the IFNG axis were previously unclear.\"},{\"question\":\"Which immune cell population was most strongly associated with IFNG in this study?\",\"answer\":\"Among major immune populations, CD8+ T cells expressed IFNG most highly.\"},{\"question\":\"What did the study find about CD38+ HLA-DR+ effector memory CD8+ T cells in CAV?\",\"answer\":\"The CD38+ HLA-DR+ CD8+ effector memory CD8+ T cell cluster was significantly increased in CAV, showed clonal expansion, increased IFNG signaling, and enhanced cytotoxicity, and it infiltrated the intima of explanted CAV coronary arteries.\"}]","Proinflammatory and cytotoxic CD38+ HLA-DR+ effector memory CD8+ T cells are peripherally expanded in human cardiac allograft vasculopathy | PDF",1790713316,76]