{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:07:57Z","timestamp":1789031277833,"version":"build-2803163510"},"reference-count":100,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Although the relevance of thymic epithelial cell\u2013thymocyte interactions for thymus function has long been emphasised, the mechanisms that govern the biology of thymic epithelial cells (TECs) are not fully understood. In other epithelial tissues, erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ligands, the Eph receptor-interacting proteins (ephrins), have been demonstrated to be important regulators of epithelial homeostasis. Accordingly, we have studied the function of Eph\/ephrin signalling in the organisation, phenotypes and function of mouse thymic epithelial cells, as well as its effects on T-cell differentiation, for over 20 years. This review provides a detailed description of these results, concluding that the absence of certain EphA\/B receptors or ephrins B generates specific phenotypes that affect T-cell differentiation and immunological function in different ways. This suggests that the proper histological organisation of the epithelial thymic stroma is not essential for normal T-cell maturation, or that at least some aspects of the process are preserved.<\/jats:p>","DOI":"10.3390\/cells15181638","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:07:41Z","timestamp":1789027661000},"page":"1638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Murine Epithelial Thymic Microenvironment Is Governed by Eph\/Ephrin Signalling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-8987","authenticated-orcid":false,"given":"Sara","family":"Montero-Herrad\u00f3n","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Histology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"Health Research Institute, Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-9818","authenticated-orcid":false,"given":"David","family":"Alfaro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Histology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"Health Research Institute, Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agust\u00edn G.","family":"Zapata","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Histology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0940-455X","authenticated-orcid":false,"given":"Javier","family":"Garc\u00eda-Ceca","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Histology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"Health Research Institute, Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0213-9626(09)70024-1","article-title":"Eph and ephrin: Key molecules for the organization and function of the thymus gland","volume":"28","author":"Alfaro","year":"2009","journal-title":"Inmunolog\u00eda"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Ceca, J., Alfaro, D., Montero-Herrad\u00f3n, S., Tobajas, E., Mu\u00f1oz, J.J., and Zapata, A.G. (2015). Eph\/Ephrins-Mediated Thymocyte\u2013Thymic Epithelial Cell Interactions Control Numerous Processes of Thymus Biology. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00333"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ydbio.2004.03.027","article-title":"Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development","volume":"271","author":"Dravis","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2005.10.034","article-title":"Ephrin-B2 Controls Cell Motility and Adhesion during Blood-Vessel-Wall Assembly","volume":"124","author":"Foo","year":"2006","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.cell.2006.04.030","article-title":"EphB Receptors Coordinate Migration and Proliferation in the Intestinal Stem Cell Niche","volume":"125","author":"Holmberg","year":"2006","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.tibs.2024.10.002","article-title":"Eph receptor signaling complexes in the plasma membrane","volume":"49","author":"Pasquale","year":"2024","journal-title":"Trends Biochem. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1007\/s00018-017-2566-1","article-title":"Ephrin ligands and Eph receptors contribution to hematopoiesis","volume":"74","author":"Tosato","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cell.2008.03.011","article-title":"Eph-Ephrin Bidirectional Signaling in Physiology and Disease","volume":"133","author":"Pasquale","year":"2008","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/dvdy.20200","article-title":"Ephrin signaling in vivo: Look both ways","volume":"232","author":"Davy","year":"2005","journal-title":"Dev. Dyn."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4049\/jimmunol.169.1.177","article-title":"Expression and Function of the Eph A Receptors and Their Ligands Ephrins A in the Rat Thymus","volume":"169","author":"Crompton","year":"2002","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1365-2567.2008.02828.x","article-title":"Alterations in the thymocyte phenotype of EphB-deficient mice largely affect the double negative cell compartment","volume":"125","author":"Alfaro","year":"2008","journal-title":"Immunology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1080\/15476278.2017.1389368","article-title":"EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells","volume":"13","author":"Zapata","year":"2017","journal-title":"Organogenesis"},{"key":"ref_13","first-page":"130","article-title":"Eph\/ephrinB signalling is involved in the survival of thymic epithelial cells","volume":"91","author":"Alfaro","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1387\/ijdb.082702jg","article-title":"On the role of Eph signalling in thymus histogenesis; EphB2\/B3 and the organizing of the thymic epithelial network","volume":"53","author":"Jimenez","year":"2009","journal-title":"Int. J. Dev. Biol."},{"key":"ref_15","unstructured":"Coles, M.C., Adams, R., Adams, S., Roderick, K., Norton, T., Wilkinson, D., and Kioussis, D. (2004, January 18\u201323). The Role of Eph Receptors and Ephrin Ligands in T Cell Development in the Thymus. Proceedings of the 12th International Congress of Immunology and 4th Annual Conference of FOCIS, Montreal, QC, Canada."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0006-291X(02)02399-9","article-title":"Developmental expression of EphB6 in the thymus: Lessons from EphB6 knockout mice","volume":"298","author":"Shimoyama","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1172\/JCI21846","article-title":"EphB6-null mutation results in compromised T cell function","volume":"114","author":"Luo","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/eji.200737097","article-title":"EphrinB1-EphB signaling regulates thymocyte-epithelium interactions involved in functional T cell development","volume":"37","author":"Alfaro","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10222","DOI":"10.1074\/jbc.M510320200","article-title":"Ephrin-B1 is critical in T-cell development","volume":"281","author":"Yu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.4049\/jimmunol.176.7.4066","article-title":"EphA Receptors Inhibit Anti-CD3-Induced Apoptosis in Thymocytes","volume":"176","author":"Freywald","year":"2006","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10150","DOI":"10.1074\/jbc.M208179200","article-title":"The EphB6 Receptor Inhibits JNK Activation in T Lymphocytes and Modulates T Cell Receptor-mediated Responses","volume":"278","author":"Freywald","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.4049\/jimmunol.167.3.1362","article-title":"Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells","volume":"167","author":"Luo","year":"2001","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1189\/jlb.1HI1114-568R","article-title":"EphB2 and EphB3 play an important role in the lymphoid seeding of murine adult thymus","volume":"98","author":"Alfaro","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_24","first-page":"87","article-title":"Trafficking to the thymus","volume":"373","author":"Zhang","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00418-016-1431-x","article-title":"Eph\/ephrin-B-mediated cell-to-cell interactions govern MTS20+ thymic epithelial cell development","volume":"146","author":"Alfaro","year":"2016","journal-title":"Histochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1189\/jlb.0210079","article-title":"EphB2-mediated interactions are essential for proper migration of T cell progenitors during fetal thymus colonization","volume":"88","author":"Alfaro","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1002\/1521-4141(200212)32:12<3745::AID-IMMU3745>3.0.CO;2-M","article-title":"Ephrin stimulation modulates T?cell chemotaxis","volume":"32","author":"Sharfe","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C189","DOI":"10.1152\/ajpcell.00314.2007","article-title":"Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis","volume":"294","author":"Kitamura","year":"2008","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1084\/jem.20082502","article-title":"Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin\/CCL25","volume":"206","author":"Gossens","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1749-6632.2010.05881.x","article-title":"Hematopoietic progenitor migration to the adult thymus","volume":"1217","author":"Zlotoff","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1182\/blood-2009-07-235721","article-title":"CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus","volume":"115","author":"Krueger","year":"2010","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1002\/eji.201445123","article-title":"Delta-like 4-mediated Notch signaling is required for early T-cell development in a three-dimensional thymic structure","volume":"45","author":"Hirano","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44976","DOI":"10.1074\/jbc.M111.316414","article-title":"Ephrinb1 and Ephrinb2 are associated with interleukin-7 receptor alpha and retard its internalization from the cell surface","volume":"286","author":"Luo","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/nri937","article-title":"A positive look at double-negative thymocytes","volume":"2","author":"Ceredig","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1084\/jem.20022135","article-title":"Differential Requirement for Mesenchyme in the Proliferation and Maturation of Thymic Epithelial Progenitors","volume":"198","author":"Jenkinson","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.4049\/jimmunol.167.4.1954","article-title":"Development of the Thymus Requires Signaling Through the Fibroblast Growth Factor Receptor R2-IIIb","volume":"167","author":"Revest","year":"2001","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18866","DOI":"10.1073\/pnas.0509741102","article-title":"Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains","volume":"102","author":"Yokote","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00418-014-1296-9","article-title":"Conditioned deletion of ephrinB1 and\/or ephrinB2 in either thymocytes or thymic epithelial cells alters the organization of thymic medulla and favors the appearance of thymic epithelial cysts","volume":"143","author":"Cejalvo","year":"2014","journal-title":"Histochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1083\/jcb.200306033","article-title":"Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus","volume":"163","author":"Henkemeyer","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1074\/jbc.M411383200","article-title":"Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase. Role of Rho family small GTPases","volume":"280","author":"Miao","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13813","DOI":"10.1073\/pnas.96.24.13813","article-title":"An Eph receptor regulates integrin activity through R-Ras","volume":"96","author":"Zou","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/ni983","article-title":"A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation","volume":"4","author":"Su","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S1074-7613(01)00180-7","article-title":"Stat3 in Thymic Epithelial Cells Is Essential for Postnatal Maintenance of Thymic Architecture and Thymocyte Survival","volume":"15","author":"Sano","year":"2001","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1080\/17402520600935097","article-title":"The Wnt Signaling Antagonist Kremen1 is Required for Development of Thymic Architecture","volume":"13","author":"Osada","year":"2006","journal-title":"J. Immunol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13383","DOI":"10.1074\/jbc.M313356200","article-title":"Identification of the Jak\/Stat proteins as novel downstream targets of EphA4 signaling in muscle: Implications in the regulation of acetylcholinesterase expression","volume":"279","author":"Lai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7992","DOI":"10.1074\/jbc.271.14.7992","article-title":"Oncogenic Neu\/ErbB-2 Increases Ets, AP-1, and NF-kB-dependent Gene Expression, and Inhibiting Ets Activation Blocks Neu-mediated Cellular Transformation","volume":"271","author":"Galang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1046\/j.1523-1747.1998.00071.x","article-title":"Effect of AP1 Transcription Factors on the Regulation of Transcription in Normal Human Epidermal Keratinocytes","volume":"110","author":"Rossi","year":"1998","journal-title":"J. Investig. Dermatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.4049\/jimmunol.169.6.2842","article-title":"Cutting Edge: Thymocyte-Independent and Thymocyte-Dependent Phases of Epithelial Patterning in the Fetal Thymus","volume":"169","author":"Klug","year":"2002","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Montero-Herrad\u00f3n, S., Garc\u00eda-Ceca, J., and Zapata, A.G. (2018). Altered Maturation of Medullary TEC in EphB-Deficient Thymi Is Recovered by RANK Signaling Stimulation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01020"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nri.2017.12","article-title":"Generation of diversity in thymic epithelial cells","volume":"17","author":"Takahama","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.immuni.2008.06.018","article-title":"The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator","volume":"29","author":"Hikosaka","year":"2008","journal-title":"Immunity"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/imr.12406","article-title":"Control of the thymic medulla and its influence on alphabetaT-cell development","volume":"271","author":"Lucas","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.4049\/jimmunol.1003533","article-title":"Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma","volume":"186","author":"Mouri","year":"2011","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/978-1-4684-9066-4_61","article-title":"Rat thymus micro-environment: An ultrastructural and functional characterization","volume":"149","author":"Duijvestijn","year":"1982","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/aja.1001700307","article-title":"Immunohistology of lymphoid and non-lymphoid cells in the thymus in relation to T lymphocyte differentiation","volume":"170","year":"1984","journal-title":"Am. J. Anat."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"von Gaudecker, B. (1986). The development of the human thymus microenvironment. The Human Thymus, Springer. Current Topics in Pathology.","DOI":"10.1007\/978-3-642-82480-7_1"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00418-017-1583-3","article-title":"Increased epithelial-free areas in thymuses with altered EphB-mediated thymocyte\u2013thymic epithelial cell interactions","volume":"148","author":"Alfaro","year":"2017","journal-title":"Histochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/BF00319429","article-title":"The effects of pregnancy on the mouse thymic epithelium","volume":"275","author":"Clarke","year":"1994","journal-title":"Cell Tissue Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e109995","DOI":"10.1371\/journal.pone.0109995","article-title":"Three Distinct Subsets of Thymic Epithelial Cells in Rats and Mice Defined by Novel Antibodies","volume":"9","author":"Sawanobori","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1155\/1993\/90759","article-title":"Epithelium-Free Area in The Thymic Cortex of Rats","volume":"3","author":"Bruijntjes","year":"1992","journal-title":"J. Immunol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0167-5699(91)90161-L","article-title":"Towards an integrated view of thymopoiesis","volume":"12","author":"Boyd","year":"1991","journal-title":"Immunol. Today"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nrm.2015.16","article-title":"Mechanisms of ephrin\u2013Eph signalling in development, physiology and disease","volume":"17","author":"Kania","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/21907","article-title":"Eph receptors and ephrins restrict cell intermingling and communication","volume":"400","author":"Mellitzer","year":"1999","journal-title":"Nature"},{"key":"ref_64","first-page":"125","article-title":"Defects in the thymic epithelial stroma of diabetes prone BB rats","volume":"14","author":"Rozing","year":"1989","journal-title":"Thymus"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.4049\/jimmunol.1201931","article-title":"Ephrin-B\u2013Dependent Thymic Epithelial Cell\u2013Thymocyte Interactions Are Necessary for Correct T Cell Differentiation and Thymus Histology Organization: Relevance for Thymic Cortex Development","volume":"190","author":"Cejalvo","year":"2013","journal-title":"J. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1006\/mcne.1996.0057","article-title":"Similarities and Differences in the Way Transmembrane-Type Ligands Interact with the Elk Subclass of Eph Receptors","volume":"8","author":"Brambilla","year":"1996","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0896-6273(00)80276-7","article-title":"Eph Receptors and Ligands Comprise Two Major Specificity Subclasses and Are Reciprocally Compartmentalized during Embryogenesis","volume":"17","author":"Gale","year":"1996","journal-title":"Neuron"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"804","DOI":"10.4049\/jimmunol.177.2.804","article-title":"Thymic Alterations in EphA4-Deficient Mice","volume":"177","author":"Alfaro","year":"2006","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1182\/blood-2006-02-004531","article-title":"Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells","volume":"108","author":"Gray","year":"2006","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1034\/j.1600-065X.2002.18903.x","article-title":"Organization of thymic medullary epithelial heterogeneity: Implications for mechanisms of epithelial differentiation","volume":"189","author":"Farr","year":"2002","journal-title":"Immunol. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1155\/1993\/56290","article-title":"Expression of The \u03b1\u03b2 T-Cell Receptor Is Necessary for The Generation of The Thymic Medulla","volume":"3","author":"Palmer","year":"1993","journal-title":"J. Immunol. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1093\/intimm\/6.9.1393","article-title":"Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes","volume":"6","author":"Shores","year":"1994","journal-title":"Int. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1006\/smim.1998.0158","article-title":"Thymic microenvironments, 3-D versus 2-D?","volume":"11","author":"Wang","year":"1999","journal-title":"Semin. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.molimm.2009.10.034","article-title":"Thymic cysts originate from Foxn1 positive thymic medullary epithelium","volume":"47","author":"Vroegindeweij","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Jin, W., Qi, S., and Luo, H. (2011). The effect of conditional EFNB1 deletion in the T cell compartment on T cell development and function. BMC Immunol., 12.","DOI":"10.1186\/1471-2172-12-68"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.molimm.2012.05.008","article-title":"T cell-specific deletion of EFNB2 minimally affects T cell development and function","volume":"52","author":"Jin","year":"2012","journal-title":"Mol. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molimm.2013.10.008","article-title":"Effect of reduced EPHB4 expression in thymic epithelial cells on thymocyte development and peripheral T cell function","volume":"58","author":"Jin","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/icb.2010.172","article-title":"The Eph\/ephrinB signal balance determines the pattern of T-cell maturation in the thymus","volume":"89","author":"Alfaro","year":"2011","journal-title":"Immunol. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Ceca, J., Montero-Herrad\u00f3n, S., and Zapata, A.G. (2020). Intrathymic Selection and Defects in the Thymic Epithelial Cell Development. Cells, 9.","DOI":"10.3390\/cells9102226"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00018-024-05197-0","article-title":"Peripheral T-cell responses of EphB2- and EphB3-deficient mice in a model of collagen-induced arthritis","volume":"81","author":"Zapata","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Wang, Y., and Zhang, C. (2019). The Roles of Liver-Resident Lymphocytes in Liver Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01582"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e55948","DOI":"10.1371\/journal.pone.0055948","article-title":"EphA4 Receptor Tyrosine Kinase Is a Modulator of Onset and Disease Severity of Experimental Autoimmune Encephalomyelitis (EAE)","volume":"8","author":"Munro","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.nbd.2016.03.013","article-title":"EphrinB1 and EphrinB2 regulate T cell chemotaxis and migration in experimental autoimmune encephalomyelitis and multiple sclerosis","volume":"91","author":"Luo","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1002\/art.39116","article-title":"Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis","volume":"67","author":"Hu","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/eji.202048952","article-title":"Towards prevention of autoimmune diseases: The example of rheumatoid arthritis","volume":"51","author":"Hensvold","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Hasegawa, H., and Matsumoto, T. (2018). Mechanisms of Tolerance Induction by Dendritic Cells In Vivo. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00350"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1146\/annurev-immunol-090222-101050","article-title":"Aire in Autoimmunity","volume":"42","author":"Miller","year":"2024","journal-title":"Annu. Rev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1016\/j.cell.2022.05.018","article-title":"Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells","volume":"185","author":"Michelson","year":"2022","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e70028","DOI":"10.1111\/imr.70028","article-title":"Thymic Mimetic Cells: Evolutionarily Ancient Mirrors of the Periphery","volume":"331","author":"Huisman","year":"2025","journal-title":"Immunol. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/s41586-018-0345-2","article-title":"Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development","volume":"559","author":"Miller","year":"2018","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.immuni.2024.11.025","article-title":"Cross-species analyses of thymic mimetic cells reveal evolutionarily ancient origins and both conserved and species-specific elements","volume":"58","author":"Huisman","year":"2024","journal-title":"Immunity"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1016\/j.febslet.2011.04.034","article-title":"Effector T cells in rheumatoid arthritis: Lessons from animal models","volume":"585","author":"Alzabin","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.4049\/jimmunol.159.11.5687","article-title":"Suppression of collagen-induced arthritis by continuous administration of IL-4","volume":"159","author":"Horsfall","year":"1997","journal-title":"J. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/ar14","article-title":"Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis","volume":"1","author":"Lubberts","year":"1999","journal-title":"Arthritis Res. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1038\/sj.gt.3301324","article-title":"Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis","volume":"7","author":"Cottard","year":"2000","journal-title":"Gene Ther."},{"key":"ref_96","first-page":"1","article-title":"Altered thymocyte development observed in EphA4-deficient mice courses with changes in both thymic epithelial and extracellular matrix organization","volume":"79","author":"Plaza","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1084\/jem.185.4.731","article-title":"Induction of the early growth response (Egr) family of transcription factors during thymic selection","volume":"185","author":"Shao","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.1242\/dev.00154","article-title":"Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning","volume":"129","author":"Davidson","year":"2002","journal-title":"Development"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.cell.2007.02.045","article-title":"p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia","volume":"129","author":"Senoo","year":"2007","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1084\/jem.20171000","article-title":"Redefining thymus medulla specialization for central tolerance","volume":"214","author":"Cosway","year":"2017","journal-title":"J. Exp. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1638\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:21:46Z","timestamp":1789028506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1638"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":100,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181638"],"URL":"https:\/\/doi.org\/10.3390\/cells15181638","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}