A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation

Pedro Ferreirinha; Camila Ribeiro; Junko Morimoto; Jonathan J. M. Landry; Minoru Matsumoto; Catarina Meireles; Andrea J. White; Izumi Ohigashi; Leonor Araújo; Vladimir Benes; Yousuke Takahama; Graham Anderson; Mitsuru Matsumoto; Nuno L. Alves

doi:10.1002/eji.202048764

A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation

Pedro Ferreirinha, Camila Ribeiro, Junko Morimoto, Jonathan J. M. Landry, Minoru Matsumoto, Catarina Meireles, Andrea J. White, Izumi Ohigashi, Leonor Araújo, Vladimir Benes, Yousuke Takahama, Graham Anderson, Mitsuru Matsumoto, Nuno L. Alves^*

^*Corresponding author for this work

Immunology and Immunotherapy

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Abstract

Autoimmune regulator⁺ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire⁺mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEC^hi(MHCII^hiCD80^hi) compartment into mTEC^A/hi (CD24⁻Sca1⁻), mTEC^B/hi (CD24⁺Sca1⁻), and mTEC^C/hi (CD24⁺Sca1⁺). While mTEC^A/hi included mostly Aire-expressing cells, mTEC^B/hi contained Aire⁺ and Aire⁻ cells and mTEC^C/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTEC^A/hi, mTEC^B/hi, and mTEC^C/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTEC^C/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.

Original language	English
Pages (from-to)	311-318
Number of pages	8
Journal	European Journal of Immunology
Volume	51
Issue number	2
Early online date	26 Aug 2020
DOIs	https://doi.org/10.1002/eji.202048764
Publication status	Published - Feb 2021

Bibliographical note

Funding Information:
This work was supported by a starting grant from the European Research Council (ERC) under the project 637843 and by FEDER ‐ Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 ‐ Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT ‐ Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI‐01‐0145‐FEDER‐029129 (PTDC/MED‐IMU/29129/2017). N.L.A is supported by the FCT program “Scientific Employment Stimulus”. M.M. is supported by the Japanese Agency for Medical Research and Development‐Core Research for Evolutional Science and Technology (JSPS KAKENHI Grant Numbers JP16K21731, JP16H06496 and JP16H05342). We thank Drs. Sofia Lamas and the caretakers from the animal facility for technical assistance. We thank Dr. Pedro Rodrigues for discussions and critical reading.

Publisher Copyright:
© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH

Keywords

autoimmune regulator
differentiation
medullary thymic epithelial cell
thymus
tolerance induction

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Ferreirinha, P., Ribeiro, C., Morimoto, J., Landry, J. J. M., Matsumoto, M., Meireles, C., White, A. J., Ohigashi, I., Araújo, L., Benes, V., Takahama, Y., Anderson, G., Matsumoto, M., & Alves, N. L. (2021). A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation. European Journal of Immunology, 51(2), 311-318. https://doi.org/10.1002/eji.202048764

@article{5fd6627a4a2c4a16ab23e4e8d9553ff2,

title = "A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation",

abstract = "Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi(MHCIIhiCD80hi) compartment into mTECA/hi (CD24−Sca1−), mTECB/hi (CD24+Sca1−), and mTECC/hi (CD24+Sca1+). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire− cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi, mTECB/hi, and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.",

keywords = "autoimmune regulator, differentiation, medullary thymic epithelial cell, thymus, tolerance induction",

author = "Pedro Ferreirinha and Camila Ribeiro and Junko Morimoto and Landry, {Jonathan J. M.} and Minoru Matsumoto and Catarina Meireles and White, {Andrea J.} and Izumi Ohigashi and Leonor Ara{\'u}jo and Vladimir Benes and Yousuke Takahama and Graham Anderson and Mitsuru Matsumoto and Alves, {Nuno L.}",

note = "Funding Information: This work was supported by a starting grant from the European Research Council (ERC) under the project 637843 and by FEDER ‐ Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 ‐ Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT ‐ Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia/Minist{\'e}rio da Ci{\^e}ncia, Tecnologia e Ensino Superior in the framework of the project POCI‐01‐0145‐FEDER‐029129 (PTDC/MED‐IMU/29129/2017). N.L.A is supported by the FCT program “Scientific Employment Stimulus”. M.M. is supported by the Japanese Agency for Medical Research and Development‐Core Research for Evolutional Science and Technology (JSPS KAKENHI Grant Numbers JP16K21731, JP16H06496 and JP16H05342). We thank Drs. Sofia Lamas and the caretakers from the animal facility for technical assistance. We thank Dr. Pedro Rodrigues for discussions and critical reading. Publisher Copyright: {\textcopyright} 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH",

year = "2021",

month = feb,

doi = "10.1002/eji.202048764",

language = "English",

volume = "51",

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Ferreirinha, P, Ribeiro, C, Morimoto, J, Landry, JJM, Matsumoto, M, Meireles, C, White, AJ, Ohigashi, I, Araújo, L, Benes, V, Takahama, Y, Anderson, G, Matsumoto, M & Alves, NL 2021, 'A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation', European Journal of Immunology, vol. 51, no. 2, pp. 311-318. https://doi.org/10.1002/eji.202048764

TY - JOUR

T1 - A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation

AU - Ferreirinha, Pedro

AU - Ribeiro, Camila

AU - Morimoto, Junko

AU - Landry, Jonathan J. M.

AU - Matsumoto, Minoru

AU - Meireles, Catarina

AU - White, Andrea J.

AU - Ohigashi, Izumi

AU - Araújo, Leonor

AU - Benes, Vladimir

AU - Takahama, Yousuke

AU - Anderson, Graham

AU - Matsumoto, Mitsuru

AU - Alves, Nuno L.

N1 - Funding Information: This work was supported by a starting grant from the European Research Council (ERC) under the project 637843 and by FEDER ‐ Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 ‐ Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT ‐ Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI‐01‐0145‐FEDER‐029129 (PTDC/MED‐IMU/29129/2017). N.L.A is supported by the FCT program “Scientific Employment Stimulus”. M.M. is supported by the Japanese Agency for Medical Research and Development‐Core Research for Evolutional Science and Technology (JSPS KAKENHI Grant Numbers JP16K21731, JP16H06496 and JP16H05342). We thank Drs. Sofia Lamas and the caretakers from the animal facility for technical assistance. We thank Dr. Pedro Rodrigues for discussions and critical reading. Publisher Copyright: © 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH

PY - 2021/2

Y1 - 2021/2

N2 - Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi(MHCIIhiCD80hi) compartment into mTECA/hi (CD24−Sca1−), mTECB/hi (CD24+Sca1−), and mTECC/hi (CD24+Sca1+). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire− cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi, mTECB/hi, and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.

AB - Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi(MHCIIhiCD80hi) compartment into mTECA/hi (CD24−Sca1−), mTECB/hi (CD24+Sca1−), and mTECC/hi (CD24+Sca1+). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire− cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi, mTECB/hi, and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.

KW - autoimmune regulator

KW - differentiation

KW - medullary thymic epithelial cell

KW - thymus

KW - tolerance induction

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A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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