IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes
Development of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.965303/full |
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| author | Cécile Apert Ariel O. Galindo-Albarrán Ariel O. Galindo-Albarrán Sarah Castan Claire Detraves Héloise Michaud Nicola McJannett Bart Haegeman Simon Fillatreau Simon Fillatreau Simon Fillatreau Bernard Malissen Georg Holländer Georg Holländer Georg Holländer Saulius Žuklys Jérémy C. Santamaria Olivier P. Joffre Paola Romagnoli Joost P. M. van Meerwijk |
| author_facet | Cécile Apert Ariel O. Galindo-Albarrán Ariel O. Galindo-Albarrán Sarah Castan Claire Detraves Héloise Michaud Nicola McJannett Bart Haegeman Simon Fillatreau Simon Fillatreau Simon Fillatreau Bernard Malissen Georg Holländer Georg Holländer Georg Holländer Saulius Žuklys Jérémy C. Santamaria Olivier P. Joffre Paola Romagnoli Joost P. M. van Meerwijk |
| author_sort | Cécile Apert |
| collection | DOAJ |
| description | Development of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it was recently shown that a substantial part of thymic Treg are cells that had recirculated from the periphery back to the thymus, troubling interpretation of these results. We therefore reassessed the involvement of IL-2 and IL-15 in the development of Treg, taking into account Treg-recirculation. At the age of three weeks, when in wt and IL-15-deficient (but not in IL-2-deficient) mice substantial amounts of recirculating Treg are present in the thymus, we found similarly reduced proportions of newly developed Treg in absence of IL-2 or IL-15, and in absence of both cytokines even less Treg developed. In neonates, when practically no recirculating Treg were found in the thymus, the absence of IL-2 led to substantially more reduced Treg-development than deficiency in IL-15. IL-2 but not IL-15 modulated the CD25, GITR, OX40, and CD73-phenotypes of the thymus-egress-competent and periphery-seeding Treg-population. Interestingly, IL-2 and IL-15 also modulated the TCR-repertoire expressed by developing Treg. Upon transfer into Treg-less Foxp3sf mice, newly developed Treg from IL-2- (and to a much lesser extent IL-15-) deficient mice suppressed immunopathology less efficiently than wt Treg. Taken together, our results firmly establish important non-redundant quantitative and qualitative roles for IL-2 and, to a lesser extent, IL-15 in intrathymic Treg-development. |
| first_indexed | 2024-04-11T21:13:57Z |
| format | Article |
| id | doaj.art-99c45be99e5148a1b68f7c4d8d930a42 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T21:13:57Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-99c45be99e5148a1b68f7c4d8d930a422022-12-22T04:02:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.965303965303IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytesCécile Apert0Ariel O. Galindo-Albarrán1Ariel O. Galindo-Albarrán2Sarah Castan3Claire Detraves4Héloise Michaud5Nicola McJannett6Bart Haegeman7Simon Fillatreau8Simon Fillatreau9Simon Fillatreau10Bernard Malissen11Georg Holländer12Georg Holländer13Georg Holländer14Saulius Žuklys15Jérémy C. Santamaria16Olivier P. Joffre17Paola Romagnoli18Joost P. M. van Meerwijk19Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceStation d’Ecologie Théorique et Expérimentale, CNRS, Moulis, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceStation d’Ecologie Théorique et Expérimentale, CNRS, Moulis, FranceInstitut Necker Enfants Malades, Inserm U1151, CNRS UMR8253, Paris, FranceUniversité de Paris Descartes, Faculté de Médecine, Paris, FranceAP-HP, Hôpital Necker-Enfants Malades, Paris, FranceCentre d’Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, Marseille, FrancePaediatric Immunology, Department of Biomedicine, University of Basel and University Children’s Hospital Basel, Basel, SwitzerlandDepartment of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomDepartment of Biosystems Science and Engineering, ETH Zurich, Basel, SwitzerlandPaediatric Immunology, Department of Biomedicine, University of Basel and University Children’s Hospital Basel, Basel, SwitzerlandToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, Toulouse, FranceDevelopment of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it was recently shown that a substantial part of thymic Treg are cells that had recirculated from the periphery back to the thymus, troubling interpretation of these results. We therefore reassessed the involvement of IL-2 and IL-15 in the development of Treg, taking into account Treg-recirculation. At the age of three weeks, when in wt and IL-15-deficient (but not in IL-2-deficient) mice substantial amounts of recirculating Treg are present in the thymus, we found similarly reduced proportions of newly developed Treg in absence of IL-2 or IL-15, and in absence of both cytokines even less Treg developed. In neonates, when practically no recirculating Treg were found in the thymus, the absence of IL-2 led to substantially more reduced Treg-development than deficiency in IL-15. IL-2 but not IL-15 modulated the CD25, GITR, OX40, and CD73-phenotypes of the thymus-egress-competent and periphery-seeding Treg-population. Interestingly, IL-2 and IL-15 also modulated the TCR-repertoire expressed by developing Treg. Upon transfer into Treg-less Foxp3sf mice, newly developed Treg from IL-2- (and to a much lesser extent IL-15-) deficient mice suppressed immunopathology less efficiently than wt Treg. Taken together, our results firmly establish important non-redundant quantitative and qualitative roles for IL-2 and, to a lesser extent, IL-15 in intrathymic Treg-development.https://www.frontiersin.org/articles/10.3389/fimmu.2022.965303/fullthymusT lymphocyteregulatory T cell (T reg)immunopathologycytokines |
| spellingShingle | Cécile Apert Ariel O. Galindo-Albarrán Ariel O. Galindo-Albarrán Sarah Castan Claire Detraves Héloise Michaud Nicola McJannett Bart Haegeman Simon Fillatreau Simon Fillatreau Simon Fillatreau Bernard Malissen Georg Holländer Georg Holländer Georg Holländer Saulius Žuklys Jérémy C. Santamaria Olivier P. Joffre Paola Romagnoli Joost P. M. van Meerwijk IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes Frontiers in Immunology thymus T lymphocyte regulatory T cell (T reg) immunopathology cytokines |
| title | IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes |
| title_full | IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes |
| title_fullStr | IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes |
| title_full_unstemmed | IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes |
| title_short | IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes |
| title_sort | il 2 and il 15 drive intrathymic development of distinct periphery seeding cd4 foxp3 regulatory t lymphocytes |
| topic | thymus T lymphocyte regulatory T cell (T reg) immunopathology cytokines |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.965303/full |
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