title: Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus.
abstract: Cortical and medullary thymic epithelial cells (cTECs and mTECs, respectively) provide inductive microenvironments for T-cell development and selection. The differentiation pathway of cTEC/mTEC lineages downstream of common bipotent progenitors at discrete stages of development remains unresolved. Using IL-7/CCRL1 dual reporter mice that identify specialized TEC subsets, we show that the stepwise acquisition of chemokine (C-C motif) receptor-like 1 (CCRL1) is a late determinant of cTEC differentiation. Although cTECs expressing high CCRL1 levels (CCRL1(hi) ) develop normally in immunocompetent and Rag2(-/-) thymi, their differentiation is partially blocked in Rag2(-/-) Il2rg(-/-) counterparts. These results unravel a novel checkpoint in cTEC maturation that is regulated by the cross-talk between TECs and immature thymocytes. Additionally, we identify new Ulex europaeus agglutinin 1 (UEA)(+) mTEC subtypes expressing intermediate CCRL1 levels (CCRL1(int) ) that conspicuously emerge in the postnatal thymus and differentially express Tnfrsf11a, Ccl21, and Aire. While rare in fetal and in Rag2(-/-) thymi, CCRL1(int) mTECs are restored in Rag2(-/-) Marilyn TCR-Tg mice, indicating that the appearance of postnatal-restricted mTECs is closely linked with T-cell selection. Our findings suggest that alternative temporally restricted routes of new mTEC differentiation contribute to the establishment of the medullary niche in the postnatal thymus.
authors: Thymus Development and Function Laboratory, Institute for Molecular and Cellular Biology, Porto, Portugal; Institute for Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
authors: Ana R
authors: AR
authors: Ribeiro
authors: Catarina
authors: C
authors: Meireles
authors: Pedro M
authors: PM
authors: Rodrigues
authors: Nuno L
authors: NL
authors: Alves
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000276:immunology*; D004847:Epithelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D054388:Receptors, CCR / Q000096:biosynthesis* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000254:growth & development* / Q000276:immunology; D059467:Transcriptome
chemical_list: C000593439:Ackr4 protein, mouse; D015415:Biomarkers; D054388:Receptors, CCR
keywords: Cortex; Medulla; Thymic epithelial cells; Thymus