The Hidden Pathway: Membrane Vitamin D Receptor Deficiency and T-Cell Senescence in Pediatric Atopic Dermatitis – A Retrospective and Cross-Sectional Investigation

Xingyuan Zhu,1 Xiaofei Gao,2 Lili Wang,3 Jianping Tang,2 Lingli Luo,1 Qiang Yu,1 Bibo Qiu,1 Chuqiang Shu,4 Xieling He4,5 1Department of Laboratory Medicine, The Affiliated Children’s Hospital of Xiangya School of Medicine, Hunan Children’s Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Dermatology, The Affiliated Children’s Hospital of Xiangya School of Medicine, Hunan Children’s Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Department of Medical Genetics, Clinical Medical Research Center for Hereditary Birth Defects and Rare Diseases in Hunan Province, The Affiliated Children’s Hospital of Xiangya School of Medicine (Hunan Children’s Hospital), Central South University, Changsha, Hunan, People’s Republic of China; 4National Health Commission Key Laboratory for Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, People’s Republic of China; 5Department of Laboratory Medicine, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Chuqiang Shu, Email [email protected] Xieling He, Email [email protected]:  Pediatric Atopic dermatitis (AD) is a common, relapsing inflammatory skin disease in children. While linked to vitamin D deficiency, the roles of T-cell senescence and vitamin D receptor (VDR) signaling remain unclear.Objective:  To explore vitamin D status, VDR expression (soluble/sVDR, membrane/mVDR, nuclear/nVDR), and T-cell senescence in pediatric AD.Methods:  Serum 25-hydroxyvitamin D (25(OH)D) levels were analyzed in 408 pediatric AD patients and matched controls. In a subset (89 patients, 35 controls), plasma sVDR was measured by ELISA. T-cell immunophenotyping, senescence markers (CD27−CD28−), and mVDR/nVDR expression were assessed via flow cytometry.Results:  Children with AD had significantly lower serum 25(OH)D (p< 0.05) and sVDR (p< 0.05). Although major T-cell subset proportions were similar, children with AD showed expanded senescent populations within CD3⁺ (p< 0.01), CD8⁺ (p< 0.05), CD4⁺ (p< 0.05), and Regulatory T (Treg) cells (p< 0.01). mVDR expression was pervasively reduced across all immune cells in pediatric AD (for CD3-, CD3+ and CD8+: p< 0.0001; for CD4+, T follicular helper (Tfh) cells: p< 0.001; for Treg: p< 0.01). Senescent cells expressed higher mVDR than non-senescent cells in both groups (NC: CD3-, p< 0.0001; CD3+ and CD8+, p< 0.01; CD4+, p< 0.001. AD: CD3-, CD3+, CD8+ and CD4+, p< 0.0001), yet overall children with AD exhibited lower mVDR levels both in non-senescent and senescent cells (non-senescent cells: CD3-, p< 0.001; CD3+ and CD4-, p< 0.0001; CD4+, p< 0.01. senescent cells:CD3-, CD3+ and CD8+, p< 0.0001; CD4+, p< 0.01). nVDR alterations were more limited, with elevation only in Tfh cells (p< 0.05) of children with AD.Conclusion:  Pediatric AD is characterized by accelerated T-cell senescence and a widespread mVDR pathway deficiency. This receptor defect, coupled with vitamin D deficiency, may drive immune dysregulation and premature T-cell aging, highlighting potential therapeutic targets in both ligand and receptor pathways.Keywords: 25-hydroxyvitamin D, vitamin D receptor, T cell, senescence, pediatric atopic dermatitis