Differential LAG3 expression in intestinal tissue reveals a dual-pathology model of steroid-refractory acute graft-versus-host disease
Abstract
IntroductionAcute graft-versus-host disease (aGVHD) of the gastrointestinal tract remains a leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation, and steroid-refractory intestinal aGVHD carries a particularly poor prognosis. CD8+ T cells are critical effectors of intestinal tissue injury, yet the molecular mechanisms underlying their pathogenic role remain incompletely understood, especially in the steroid-refractory state.MethodsThis study aimed to identify key biomarker genes associated with CD8+ T cell-mediated intestinal aGVHD and to characterize their expression dynamics in the steroid-refractory state. Integrative bioinformatics analysis was performed using the Gene Expression Omnibus dataset GSE79083 (a CD8+ T cell-dependent murine aGVHD model), with a human dataset (GSE134662) for independent validation. Hub genes were prioritized through protein–protein interaction network analysis and random forest machine learning. A murine aGVHD model was established for validation via clinical score, qRT-PCR, histopathology, and immunofluorescence double staining.ResultsLag3 was identified as the top-ranked gene with high diagnostic discrimination. In the murine model, Lag3 was markedly upregulated in intestinal tissue of the aGVHD group, and immunofluorescence confirmed CD8+ LAG3+ T cell infiltration of the intestinal mucosa. Notably, the steroid-refractory group exhibited more severe colonic histopathological injury. In this group, Lag3 expression was significantly lower than in the aGVHD group despite persistent CD8+ T cell infiltration. A similar expression pattern was observed in the human dataset.ConclusionThe reduction of Lag3 despite persistent severe tissue injury suggests that glucocorticoid-resistant CD8+ T cells may have escaped checkpoint-mediated restraint. These findings suggest a dual-pathology framework for steroid-refractory intestinal aGVHD, involving both effector mechanisms independent of LAG3 and impaired epithelial repair. Whether targeting both processes in combination would be beneficial remains to be tested.
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BibTeX
@article{xia2026differential,
title = {{Differential LAG3 expression in intestinal tissue reveals a dual-pathology model of steroid-refractory acute graft-versus-host disease}},
author = {Qiaoqiao Xia and Yuting Liu and Wenying Ning and Yunyan He},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1973310},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973310},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Differential LAG3 expression in intestinal tissue reveals a dual-pathology model of steroid-refractory acute graft-versus-host disease
AU - Qiaoqiao Xia
AU - Yuting Liu
AU - Wenying Ning
AU - Yunyan He
PY - 2026
DA - 2026/11/03
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973310
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973310
AB - IntroductionAcute graft-versus-host disease (aGVHD) of the gastrointestinal tract remains a leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation, and steroid-refractory intestinal aGVHD carries a particularly poor prognosis. CD8+ T cells are critical effectors of intestinal tissue injury, yet the molecular mechanisms underlying their pathogenic role remain incompletely understood, especially in the steroid-refractory state.MethodsThis study aimed to identify key biomarker genes associated with CD8+ T cell-mediated intestinal aGVHD and to characterize their expression dynamics in the steroid-refractory state. Integrative bioinformatics analysis was performed using the Gene Expression Omnibus dataset GSE79083 (a CD8+ T cell-dependent murine aGVHD model), with a human dataset (GSE134662) for independent validation. Hub genes were prioritized through protein–protein interaction network analysis and random forest machine learning. A murine aGVHD model was established for validation via clinical score, qRT-PCR, histopathology, and immunofluorescence double staining.ResultsLag3 was identified as the top-ranked gene with high diagnostic discrimination. In the murine model, Lag3 was markedly upregulated in intestinal tissue of the aGVHD group, and immunofluorescence confirmed CD8+ LAG3+ T cell infiltration of the intestinal mucosa. Notably, the steroid-refractory group exhibited more severe colonic histopathological injury. In this group, Lag3 expression was significantly lower than in the aGVHD group despite persistent CD8+ T cell infiltration. A similar expression pattern was observed in the human dataset.ConclusionThe reduction of Lag3 despite persistent severe tissue injury suggests that glucocorticoid-resistant CD8+ T cells may have escaped checkpoint-mediated restraint. These findings suggest a dual-pathology framework for steroid-refractory intestinal aGVHD, involving both effector mechanisms independent of LAG3 and impaired epithelial repair. Whether targeting both processes in combination would be beneficial remains to be tested.
SN - 1664-3224
ER -