title: An essential role for medullary thymic epithelial cells during the intrathymic development of invariant NKT cells.
abstract: In the thymus, interactions with both cortical and medullary microenvironments regulate the development of self-tolerant conventional CD4(+) and CD8(+) αβT cells expressing a wide range of αβTCR specificities. Additionally, the cortex is also required for the development of invariant NKT (iNKT) cells, a specialized subset of T cells that expresses a restricted αβTCR repertoire and is linked to the regulation of innate and adaptive immune responses. Although the role of the cortex in this process is to enable recognition of CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors, the requirements for additional thymus microenvironments during iNKT cell development are unknown. In this study, we reveal a role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus. This requirement for mTECs correlates with their expression of genes required for IL-15 trans-presentation, and we show that soluble IL-15/IL-15Rα complexes restore iNKT cell development in the absence of mTECs. Furthermore, mTEC development is abnormal in iNKT cell-deficient mice, and early stages in iNKT cell development trigger receptor activator for NF-κB ligand-mediated mTEC development. Collectively, our findings demonstrate that intrathymic iNKT cell development requires stepwise interactions with both the cortex and the medulla, emphasizing the importance of thymus compartmentalization in the generation of both diverse and invariant αβT cells. Moreover, the identification of a novel requirement for iNKT cells in thymus medulla development further highlights the role of both innate and adaptive immune cells in thymus medulla formation.
authors: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Andrea J
authors: AJ
authors: White
authors: William E
authors: WE
authors: Jenkinson
authors: Jennifer E
authors: JE
authors: Cowan
authors: Sonia M
authors: SM
authors: Parnell
authors: Andrea
authors: A
authors: Bacon
authors: Nick D
authors: ND
authors: Jones
authors: Eric J
authors: EJ
authors: Jenkinson
authors: Graham
authors: G
authors: Anderson
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D060833:Cellular Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005434:Flow Cytometry; D019409:Interleukin-15 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000276:immunology / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053647:Receptors, Interleukin-15; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D051841:Transcription Factor RelB