Up-regulation of IL-7, stromal-derived factor-1 alpha, thymus-expressed chemokine, and secondary lymphoid tissue chemokine gene expression in the stromal cells in response to thymocyte depletion: implication for thymus reconstitution.
Three in vivo adult mouse models were established to study which signals are required to restore the postnatal thymus. Single administration of dexamethasone, estradiol, or exposure to sublethal dose of gamma irradiation served as prototype thymus-ablating therapies. In all models, transient thymic atrophy was manifested due to the loss of the predominant portion of CD4- CD8- double negative and CD4+ CD8+ double positive thymocytes and was followed by a complete regeneration of the thymuses. Acute atrophy/regeneration was observed in the dexamethasone and irradiation models; in the estradiol-treated animals, slow kinetics of atrophy and regeneration was observed. Importantly, in both acute and chronic models, high levels of IL-7 mRNA were detected in the thymuses isolated from mice during maximum atrophy. In addition, chemokine gene array analysis of involuted thymuses revealed high levels of mRNA expression of stromal-derived factor-1alpha (SDF-1alpha), thymus-expressed chemokine (TECK), and secondary lymphoid tissue chemokine (SLC) but not of other chemokines. The levels of IL-7, SDF-1alpha, TECK, and SLC mRNA inversely correlated with the kinetics of regeneration. RT-PCR analysis of stromal cells purified from involuted thymuses confirmed increased IL-7, SDF-1alpha, and SLC gene expression in MHC class II+ CD45- epithelial cells and increased IL-7 and TECK gene expression in class II+ CD45+ CD11c+ dendritic cells. Thus, our data showed for the first time that expression of IL-7, SDF-1alpha, TECK, and SLC mRNA is induced in the thymic stroma during T cell depletion and may play an important role in the reconstitution of the adult thymus.
Zubkova
Iryna
I
Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Mostowski
Howard
H
Zaitseva
Marina
M
D000818:Animals; D001284:Atrophy; D002453:Cell Cycle / Q000276:immunology; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D014916:Whole-Body Irradiation
C515479:Ccl21c protein, mouse; C491541:Ccl25 protein, mouse; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D015851:Interleukin-7; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D004958:Estradiol; D003907:Dexamethasone