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Using mass cytometry and donor-derived MHC tetramers, it identifies Areg+Tr1 and EGFRhi exhausted EGFR+TOX+Nur77+TCF-1 subsets as dominant allospecific populations in tolerant recipients. Trajectory and cell-cell communication analyses show antigen-experienced effector memory T cells differentiate into suppressive Tr1-like and Tex-like states via the Areg–EGFR axis. Gene silencing indicates Tr1 cells drive metabolic suppression and epigenetic reprogramming of CD4+ T cells through a Nur77-dependent pathway, defining a Tr1–EGFR+Teff immunoregulatory axis in transplant tolerance.",{"@graph":69,"@context":123},[70,84,106],{"@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/allospecific-splenic-tr1-cells-drive-effector-t-cell-exhaustion-through-up-regulated-areg-egfr-signaling-to-promote-transplant-tolerance/449557/",{"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/allospecific-splenic-tr1-cells-drive-effector-t-cell-exhaustion-through-up-regulated-areg-egfr-signaling-to-promote-transplant-tolerance/449557.png","ImageObject",300,407,{"name":92,"@type":93},"Indoniesian Boy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main goal of inducing transplant tolerance in this work?","Question",{"text":113,"@type":114},"Achieve stable, drug-free tolerance to allogeneic transplants by understanding the mechanisms that regulate effector T cell responses and reduce graft rejection risk.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do allospecific Tr1 cells relate to effector T cell exhaustion according to the findings?",{"text":118,"@type":114},"Areg+Tr1 cells and EGFRhi terminally exhausted EGFR+TOX+Nur77+TCF-1 (Tex) subsets dominate in tolerant recipients, and effector memory T cells differentiate into suppressive Tr1 and Tex-like states.",{"name":120,"@type":111,"acceptedAnswer":121},"What signaling pathway drives the regulatory effect described in the study?",{"text":122,"@type":114},"Tr1 cells use Areg-EGFR signaling to induce metabolic suppression and epigenetic reprogramming of CD4+ T cells through a Nur77-dependent pathway.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},449557,1790816351,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},962090760608,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","IMMUNOLOGY  \nAllospecific splenic Tr1 cells drive effectorT cell exhaustion through up-regulated Areg-EGFR signaling to promote transplant tolerance  \nAmar Singh1*, Adam Herman2, Devanjan Dey1, Samuel Menge1, Shilpi Singh3, Anna Tran1, Anders Matson1, Ahmed Mourad1, Parthasarathy Rangarajan1, Ravi Masuria1, Naoya Sato1, Sarah Vadnais1, Joseph Sushil Rao1, Gatikrushna Singh3, Melanie L. Graham4,  \nSabarinathan Ramachandran1*, Bernhard J. Hering1*  \nInducing stable tolerance to transplants remains a challenge in immunology. Previously, we induced tolerance to allogeneic islets in nonhuman primates by preemptive alloantigen delivery to antigen-presenting cells in situ. Here, mass cytometry phenotyping with incorporated donor-derived MHC-I peptide–loaded MHC-II tetramers revealed accumulation of allospecific CD4+ T cell clusters in the spleen of tolerant recipients. Areg+Tr1 regulatory and terminally exhausted EGFRhiT (Tex) cells represented the predominant allospecific subsets. Trajectory analysis showed that antigen-experienced effector memory T cells differentiated into suppressive Areg+Tr1 and EGFR+TOX+Nur77+TCF-1 − Tex subsets. Cell-cell communication mapping showed that exhausted and effector memory T cells engaged with allospecific Tr1 cells via the Areg-EGFR axis. Gene silencing studies confirmed that Tr1 cells use Areg-EGFR signaling to drive the metabolic suppression and epigenetic reprogramming of CD4+ T cells through a Nur77-dependent pathway. These findings point to the splenic Areg+Tr1 cell-EGFR+Teff cell axis asa critical immunoregulatory pathway in peripheral transplant tolerance.  \ncopyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S.  \nGovernment Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) .  \nINTRODUCTION  \nPancreatic islet transplants can restore near-normal blood glucose control in individuals with type 1 diabetes (1) . However, the overall benefits of this therapy are often compromised by the toxic side effects ofthe immunosuppressive drugs required to prevent graft rejection. To enable widespread adoption of islet replacement therapies, it is essential to develop strategies that eliminate the need for long-term immunosuppression.  \nTo address this challenge, we induced immune tolerance to allogeneic islet transplants in nonhuman primates (NHPs) by preemptively delivering alloantigen in the form of apoptotic donor leukocyte (ADL) infusions under induction immunosuppression. This strategy resulted in sustained, drug-free survival of islet allografts. The mechanisms of tolerance we documented included deletion of alloreactive T cells, expansion of interleukin-10 (IL-10)– producing type 1 regulatory (Tr1) cells, and recruitment of Tr1 cells to the allograft (2). According to prior studies, efferocytosis of cells in early apoptosis elicits robust anti-inflammatory and immunoregulatory effects on antigen-presenting cells (APCs) . This process facilitates the deletion or reprogramming of antigen-experienced T cells into Foxp3+ regulatory T cells (Treg cells) and IL-10–secreting Tr1 cells that promote peripheral tolerance to antigens derived from the engulfed apoptotic material (3) . Gaining deeper insights into the microenvironments and mechanisms that drive the differentiation of Tr1 cells—and their ability to modulate effector T cell (Teff) responses—could substantially advance the clinical translation of  \n1Schulze diabetes institute, department of Surgery, University of Minnesota, Minneapolis, Mn 55455, USA. 2Minnesota Supercomputing institute, University of Minnesota, Minneapolis, Mn 55455, USA. 3department of neurosurgery, University of Minnesota, Minneapolis, Mn 55455, USA. 4Preclinical Research center, department of Surgery, University of Minnesota, Minneapolis, Mn 55455, USA.  \n*[corresponding author. email:](corresponding author. email:) [singh423@umn.edu](singh4","cbCaivmwv0oNgkiA","https://ap.wps.com/l/cbCaivmwv0oNgkiA","pdf",9875726,17,"English","# Introduction\n## Inducing tolerance to islet transplants and the need to avoid long-term immunosuppression\n## Mechanisms of Tr1-mediated tolerance and links to effector exhaustion and metabolic restraint\n## How antigen delivery shapes APC–T cell interactions and tissue localization","[{\"question\":\"What is the main goal of inducing transplant tolerance in this work?\",\"answer\":\"Achieve stable, drug-free tolerance to allogeneic transplants by understanding the mechanisms that regulate effector T cell responses and reduce graft rejection risk.\"},{\"question\":\"How do allospecific Tr1 cells relate to effector T cell exhaustion according to the findings?\",\"answer\":\"Areg+Tr1 cells and EGFRhi terminally exhausted EGFR+TOX+Nur77+TCF-1 (Tex) subsets dominate in tolerant recipients, and effector memory T cells differentiate into suppressive Tr1 and Tex-like states.\"},{\"question\":\"What signaling pathway drives the regulatory effect described in the study?\",\"answer\":\"Tr1 cells use Areg-EGFR signaling to induce metabolic suppression and epigenetic reprogramming of CD4+ T cells through a Nur77-dependent pathway.\"}]","Allospecific splenic Tr1 cells drive effector T cell exhaustion through up-regulated Areg-EGFR signaling to promote transplant tolerance | PDF",1790730569,43]