Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms
ABSTRACT Regulatory T cell (Treg)‐derived extracellular vesicles (EVs) represent a contact‐independent mechanism by which Tregs suppress dysregulated immune responses. These EVs carry diverse immunomodulatory molecules, including CD73, an ectoenzyme that hydrolyses AMP into adenosine. Adenosine subs...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Journal of Extracellular Vesicles |
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| Online Access: | https://doi.org/10.1002/jev2.70118 |
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| author | Carolina Rojas Michelle García Luis González‐Osuna Mauricio Campos‐Mora Enrique Ponce deLeón Alfredo Sierra‐Cristancho Claudia Terraza Cristian Cortez Luis Daniel Sansores‐España Paola Carvajal Jordan Bazoer Qi Peng Charlotte Lawson Lesley A. Smyth Karina Pino‐Lagos Rolando Vernal |
| author_facet | Carolina Rojas Michelle García Luis González‐Osuna Mauricio Campos‐Mora Enrique Ponce deLeón Alfredo Sierra‐Cristancho Claudia Terraza Cristian Cortez Luis Daniel Sansores‐España Paola Carvajal Jordan Bazoer Qi Peng Charlotte Lawson Lesley A. Smyth Karina Pino‐Lagos Rolando Vernal |
| author_sort | Carolina Rojas |
| collection | DOAJ |
| description | ABSTRACT Regulatory T cell (Treg)‐derived extracellular vesicles (EVs) represent a contact‐independent mechanism by which Tregs suppress dysregulated immune responses. These EVs carry diverse immunomodulatory molecules, including CD73, an ectoenzyme that hydrolyses AMP into adenosine. Adenosine subsequently acts as a potent immunosuppressive mediator that inhibits effector CD4⁺ T cell activation and controls pathological inflammation. Periodontitis is a highly prevalent inflammatory disease characterised by the accumulation of IL‐17A‐expressing CD4⁺ T cells in response to dysbiotic oral bacterial biofilms, ultimately leading to RANKL‐mediated alveolar bone resorption and tooth loss. We tested the hypothesis that CD73⁺ Treg‐derived EVs, isolated from Tregs induced with polarising cytokines in the presence of retinoic acid, could limit inflammation and prevent alveolar bone loss in periodontitis. Our findings demonstrate that Tregs induced with polarising cytokines in the presence of retinoic acid express high levels of CD73 and secrete adenosine‐producing suppressive CD73+ EVs. Furthermore, local administration of these CD73⁺ Treg‐derived EVs in a murine periodontitis model reduced activated CD4⁺ T cell infiltration, decreased IL‐17A and RANKL expression, and attenuated osteoclast‐mediated alveolar bone loss. In conclusion, retinoic acid‐induced Treg‐derived EVs suppress CD4⁺ T cell‐driven inflammation and ameliorate periodontitis, at least in part through CD73/adenosine‐dependent immunomodulatory mechanisms. |
| format | Article |
| id | doaj-art-6c909ce885fa4849b6f87f7b0b75dbbd |
| institution | DOAJ |
| issn | 2001-3078 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj-art-6c909ce885fa4849b6f87f7b0b75dbbd2025-08-20T03:08:52ZengWileyJournal of Extracellular Vesicles2001-30782025-07-01147n/an/a10.1002/jev2.70118Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory MechanismsCarolina Rojas0Michelle García1Luis González‐Osuna2Mauricio Campos‐Mora3Enrique Ponce deLeón4Alfredo Sierra‐Cristancho5Claudia Terraza6Cristian Cortez7Luis Daniel Sansores‐España8Paola Carvajal9Jordan Bazoer10Qi Peng11Charlotte Lawson12Lesley A. Smyth13Karina Pino‐Lagos14Rolando Vernal15Laboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileCentro de Investigación e Innovación Biomédica, Faculty of Medicine Universidad de Los Andes Santiago ChileDepartamento de Rehabilitación Oral, Faculty of Dentistry Universidad de Chile Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileEscuela de Tecnología Médica, Faculty of Sciences Pontificia Universidad Católica de Valparaíso Valparaíso ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileSchool of Medicine and Biomedical Sciences University of West London London UKCentre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology King's College London London UKComparative Biomedical Sciences Royal Veterinary College London UKSchool of Medicine and Biomedical Sciences University of West London London UKCentro de Investigación e Innovación Biomédica, Faculty of Medicine Universidad de Los Andes Santiago ChileLaboratorio de Biología Periodontal, Faculty of Dentistry Universidad de Chile Santiago ChileABSTRACT Regulatory T cell (Treg)‐derived extracellular vesicles (EVs) represent a contact‐independent mechanism by which Tregs suppress dysregulated immune responses. These EVs carry diverse immunomodulatory molecules, including CD73, an ectoenzyme that hydrolyses AMP into adenosine. Adenosine subsequently acts as a potent immunosuppressive mediator that inhibits effector CD4⁺ T cell activation and controls pathological inflammation. Periodontitis is a highly prevalent inflammatory disease characterised by the accumulation of IL‐17A‐expressing CD4⁺ T cells in response to dysbiotic oral bacterial biofilms, ultimately leading to RANKL‐mediated alveolar bone resorption and tooth loss. We tested the hypothesis that CD73⁺ Treg‐derived EVs, isolated from Tregs induced with polarising cytokines in the presence of retinoic acid, could limit inflammation and prevent alveolar bone loss in periodontitis. Our findings demonstrate that Tregs induced with polarising cytokines in the presence of retinoic acid express high levels of CD73 and secrete adenosine‐producing suppressive CD73+ EVs. Furthermore, local administration of these CD73⁺ Treg‐derived EVs in a murine periodontitis model reduced activated CD4⁺ T cell infiltration, decreased IL‐17A and RANKL expression, and attenuated osteoclast‐mediated alveolar bone loss. In conclusion, retinoic acid‐induced Treg‐derived EVs suppress CD4⁺ T cell‐driven inflammation and ameliorate periodontitis, at least in part through CD73/adenosine‐dependent immunomodulatory mechanisms.https://doi.org/10.1002/jev2.701185’‐nucleotidaseadenosineextracellular vesiclesperiodontitisregulatory T cellretinoic acid |
| spellingShingle | Carolina Rojas Michelle García Luis González‐Osuna Mauricio Campos‐Mora Enrique Ponce deLeón Alfredo Sierra‐Cristancho Claudia Terraza Cristian Cortez Luis Daniel Sansores‐España Paola Carvajal Jordan Bazoer Qi Peng Charlotte Lawson Lesley A. Smyth Karina Pino‐Lagos Rolando Vernal Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms Journal of Extracellular Vesicles 5’‐nucleotidase adenosine extracellular vesicles periodontitis regulatory T cell retinoic acid |
| title | Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms |
| title_full | Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms |
| title_fullStr | Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms |
| title_full_unstemmed | Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms |
| title_short | Induced Treg‐Derived Extracellular Vesicles Suppress CD4+ T‐Cell‐Mediated Inflammation and Ameliorate Bone Loss During Periodontitis Partly Through CD73/Adenosine‐Dependent Immunomodulatory Mechanisms |
| title_sort | induced treg derived extracellular vesicles suppress cd4 t cell mediated inflammation and ameliorate bone loss during periodontitis partly through cd73 adenosine dependent immunomodulatory mechanisms |
| topic | 5’‐nucleotidase adenosine extracellular vesicles periodontitis regulatory T cell retinoic acid |
| url | https://doi.org/10.1002/jev2.70118 |
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