Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells

The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells...

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Published inThe Journal of immunology (1950) Vol. 185; no. 8; pp. 4769 - 4776
Main Authors White, Andrea J, Nakamura, Kyoko, Jenkinson, William E, Saini, Manoj, Sinclair, Charles, Seddon, Benedict, Narendran, Parth, Pfeffer, Klaus, Nitta, Takeshi, Takahama, Yousuke, Caamano, Jorge H, Lane, Peter J L, Jenkinson, Eric J, Anderson, Graham
Format Journal Article
LanguageEnglish
Published United States 15.10.2010
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Abstract The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic mouse line--in which positive selection can be temporally controlled--demonstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to activation of the LTα-LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
AbstractList The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic mouse line--in which positive selection can be temporally controlled--demonstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to activation of the LTα-LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire + mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall’s corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire + mTEC development, use of an inducible ZAP70 transgenic mouse line—in which positive selection can be temporally controlled—demonstrates that the emergence of involucrin + mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire + mTECs depends upon RANK signaling, continued mTEC development to the involucrin + stage maps to activation of the LTα–LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire+ mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire+ mTEC development, use of an inducible ZAP70 transgenic mouse line-in which positive selection can be temporally controlled-demonstrates that the emergence of involucrin+ mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire+ mTECs depends upon RANK signaling, continued mTEC development to the involucrin+ stage maps to activation of the LT alpha -LT beta R axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
Author Nitta, Takeshi
Caamano, Jorge H
Narendran, Parth
Seddon, Benedict
Lane, Peter J L
Nakamura, Kyoko
Pfeffer, Klaus
Saini, Manoj
Jenkinson, William E
Anderson, Graham
Takahama, Yousuke
Jenkinson, Eric J
White, Andrea J
Sinclair, Charles
AuthorAffiliation School of Clinical and Experimental Medicine, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine University, Dusseldorf, Germany
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan
Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham
Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, United Kingdom
AuthorAffiliation_xml – name: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, United Kingdom
– name: Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan
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– name: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham
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Snippet The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic...
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StartPage 4769
SubjectTerms AIRE Protein
Animals
Cell Differentiation - immunology
Cell Separation
Epithelial Cells - cytology
Flow Cytometry
Fluorescent Antibody Technique
Humans
Lymphotoxin-alpha - immunology
Lymphotoxin-alpha - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Confocal
Protein Precursors - immunology
Protein Precursors - metabolism
Receptors, Tumor Necrosis Factor - immunology
Receptors, Tumor Necrosis Factor - metabolism
Self Tolerance - immunology
Signal Transduction - immunology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Thymus Gland - cytology
Transcription Factors - immunology
Transcription Factors - metabolism
Title Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells
URI https://www.ncbi.nlm.nih.gov/pubmed/20861360
https://www.proquest.com/docview/756823739
https://search.proquest.com/docview/856770650
https://pubmed.ncbi.nlm.nih.gov/PMC3826119
Volume 185
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