{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:51:41Z","timestamp":1792705901525,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82241221"],"award-info":[{"award-number":["82241221"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tertiary lymphoid structure (TLS) is a neogenized, ectopic lymphoid aggregate found in infected, autoimmune and tumour tissues with an activated adaptive immune response. However, a comprehensive understanding of the pathological role, function, and formation of TLS in allograft rejection remains incomplete.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We enrolled two large retrospective cohorts of liver biopsy (LB) after pediatric living donor liver transplantation (LDLT) and developed a deep learning pathomics (DLP) model. Gene expression profiles and corresponding clinical information of 590 cases were enrolled from three transcriptomic databases, including cohort-GSE193135 (n=337), cohort-GSE145780 (n=235), cohort-Renji (n=18). ESTIMATE, CIBERSORT, XCELL and MCP analyses were performed to visualize the immune landscape. Single-cell RNA-sequencing (scRNA-seq) analysis of 11 LBs after LDLT and multiplexed immunohistochemistry (mIHC) were performed to validate the discoveries of bioinformatics analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We provided evidence that increased TLS in the liver was closely correlated with allograft rejection, fibrosis, and declined liver function. ScRNA-seq and\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture analysis revealed that TLS form through the differentiation of atypical memory B (AtM B) cells via the JAK-STAT signalling pathway, stimulated by IFN-\u03b3 from exhausted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T effector memory (T\n                      <jats:sub>EM<\/jats:sub>\n                      ) cells. The presence of TLS resulted in IgG accumulation, initiating pathological antibody-dependent cell-mediated phagocytosis (ADCP) of apoptotic hepatocytes by CD68\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. Preclinically, blocking JAK1\/3 or knocking out\n                      <jats:italic>Lta<\/jats:italic>\n                      in mice limited TLS formation and attenuated allograft rejection in mouse orthotopic liver transplantation models, informing novel therapeutics for allograft rejection pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We proposed an efficient DLP model for predicting allograft rejection, and revealed an unexpected immunological mechanism of TLS in allograft rejection livers and clarified an IFN-\u03b3-JAK-STAT-dependent circuit that could be targeted with drugs and transformed AtM B cells into potent instigators of hepatocellular injury in allograft rejection.<\/jats:p>\n                  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