Distinct functions and transcriptional signatures in orally induced regulatory T cell populations
Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1278184/full |
| _version_ | 1797648851994148864 |
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| author | Moanaro Biswas Kaman So Thais B. Bertolini Preethi Krishnan Jyoti Rana Maite Muñoz-Melero Farooq Syed Sandeep R. P. Kumar Hongyu Gao Xiaoling Xuei Cox Terhorst Henry Daniell Sha Cao Roland W. Herzog |
| author_facet | Moanaro Biswas Kaman So Thais B. Bertolini Preethi Krishnan Jyoti Rana Maite Muñoz-Melero Farooq Syed Sandeep R. P. Kumar Hongyu Gao Xiaoling Xuei Cox Terhorst Henry Daniell Sha Cao Roland W. Herzog |
| author_sort | Moanaro Biswas |
| collection | DOAJ |
| description | Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration. Whilst both FoxP3+LAP+ and FoxP3-LAP+ CD4+ T cells express membrane-bound TGF-β (latency associated peptide, LAP), phenotypic, functional, and single cell transcriptomic analyses reveal distinct characteristics in the two subsets. As judged by an increase in IL-2Rα and TCR signaling, elevated expression of co-inhibitory receptor molecules and upregulation of the TGFβ and IL-10 signaling pathways, FoxP3+LAP+ cells are an activated form of FoxP3+LAP- Treg. Whereas FoxP3-LAP+ cells express low levels of genes involved in TCR signaling or co-stimulation, engagement of the AP-1 complex members Jun/Fos and Atf3 is most prominent, consistent with potent IL-10 production. Single cell transcriptomic analysis further reveals that engagement of the Jun/Fos transcription factors is requisite for mediating TGFβ expression. This can occur via an Il2ra dependent or independent process in FoxP3+LAP+ or FoxP3-LAP+ cells respectively. Surprisingly, both FoxP3+LAP+ and FoxP3-LAP+ cells potently suppress and induce FoxP3 expression in CD4+ conventional T cells. In this process, FoxP3-LAP+ cells may themselves convert to FoxP3+ Treg. We conclude that orally induced suppression is dependent on multiple regulatory cell types with complementary and interconnected roles. |
| first_indexed | 2024-03-11T15:37:56Z |
| format | Article |
| id | doaj.art-305eae01744641ecb9a275cdec627bbe |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T15:37:56Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-305eae01744641ecb9a275cdec627bbe2023-10-26T13:40:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12781841278184Distinct functions and transcriptional signatures in orally induced regulatory T cell populationsMoanaro Biswas0Kaman So1Thais B. Bertolini2Preethi Krishnan3Jyoti Rana4Maite Muñoz-Melero5Farooq Syed6Sandeep R. P. Kumar7Hongyu Gao8Xiaoling Xuei9Cox Terhorst10Henry Daniell11Sha Cao12Roland W. Herzog13Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, CanadaHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesCenter for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United StatesCenter for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United StatesDivision of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, United StatesDepartment of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesOral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration. Whilst both FoxP3+LAP+ and FoxP3-LAP+ CD4+ T cells express membrane-bound TGF-β (latency associated peptide, LAP), phenotypic, functional, and single cell transcriptomic analyses reveal distinct characteristics in the two subsets. As judged by an increase in IL-2Rα and TCR signaling, elevated expression of co-inhibitory receptor molecules and upregulation of the TGFβ and IL-10 signaling pathways, FoxP3+LAP+ cells are an activated form of FoxP3+LAP- Treg. Whereas FoxP3-LAP+ cells express low levels of genes involved in TCR signaling or co-stimulation, engagement of the AP-1 complex members Jun/Fos and Atf3 is most prominent, consistent with potent IL-10 production. Single cell transcriptomic analysis further reveals that engagement of the Jun/Fos transcription factors is requisite for mediating TGFβ expression. This can occur via an Il2ra dependent or independent process in FoxP3+LAP+ or FoxP3-LAP+ cells respectively. Surprisingly, both FoxP3+LAP+ and FoxP3-LAP+ cells potently suppress and induce FoxP3 expression in CD4+ conventional T cells. In this process, FoxP3-LAP+ cells may themselves convert to FoxP3+ Treg. We conclude that orally induced suppression is dependent on multiple regulatory cell types with complementary and interconnected roles.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1278184/fullFoxP3+ regulatory T cellslatency associated peptide (LAP)oral toleranceantidrug antibodies (ADA)single cell RNA and transcriptome sequencing |
| spellingShingle | Moanaro Biswas Kaman So Thais B. Bertolini Preethi Krishnan Jyoti Rana Maite Muñoz-Melero Farooq Syed Sandeep R. P. Kumar Hongyu Gao Xiaoling Xuei Cox Terhorst Henry Daniell Sha Cao Roland W. Herzog Distinct functions and transcriptional signatures in orally induced regulatory T cell populations Frontiers in Immunology FoxP3+ regulatory T cells latency associated peptide (LAP) oral tolerance antidrug antibodies (ADA) single cell RNA and transcriptome sequencing |
| title | Distinct functions and transcriptional signatures in orally induced regulatory T cell populations |
| title_full | Distinct functions and transcriptional signatures in orally induced regulatory T cell populations |
| title_fullStr | Distinct functions and transcriptional signatures in orally induced regulatory T cell populations |
| title_full_unstemmed | Distinct functions and transcriptional signatures in orally induced regulatory T cell populations |
| title_short | Distinct functions and transcriptional signatures in orally induced regulatory T cell populations |
| title_sort | distinct functions and transcriptional signatures in orally induced regulatory t cell populations |
| topic | FoxP3+ regulatory T cells latency associated peptide (LAP) oral tolerance antidrug antibodies (ADA) single cell RNA and transcriptome sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1278184/full |
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