Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis
Abstract Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell tran...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-05-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-00995-1 |
| _version_ | 1797811892004061184 |
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| author | Min-Ji Cho Hong-Gyun Lee Jae-Won Yoon Gil-Ran Kim Ja-Hyun Koo Reshma Taneja Brian T. Edelson You Jeong Lee Je-Min Choi |
| author_facet | Min-Ji Cho Hong-Gyun Lee Jae-Won Yoon Gil-Ran Kim Ja-Hyun Koo Reshma Taneja Brian T. Edelson You Jeong Lee Je-Min Choi |
| author_sort | Min-Ji Cho |
| collection | DOAJ |
| description | Abstract Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1β without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner. |
| first_indexed | 2024-03-13T07:30:29Z |
| format | Article |
| id | doaj.art-6382e334850643cbaedf9b44db87539e |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-13T07:30:29Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-6382e334850643cbaedf9b44db87539e2023-06-04T11:07:29ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-05-015551033104510.1038/s12276-023-00995-1Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axisMin-Ji Cho0Hong-Gyun Lee1Jae-Won Yoon2Gil-Ran Kim3Ja-Hyun Koo4Reshma Taneja5Brian T. Edelson6You Jeong Lee7Je-Min Choi8Department of Life Science, College of Natural Sciences, Hanyang UniversityDepartment of Life Science, College of Natural Sciences, Hanyang UniversityDepartment of Life Science, College of Natural Sciences, Hanyang UniversityDepartment of Life Science, College of Natural Sciences, Hanyang UniversityDepartment of Life Science, College of Natural Sciences, Hanyang UniversityDepartment of Physiology and Healthy Longevity Translation Research Program, Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of MedicineResearch Institute of Pharmaceutical Sciences, Seoul National UniversityDepartment of Life Science, College of Natural Sciences, Hanyang UniversityAbstract Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1β without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner.https://doi.org/10.1038/s12276-023-00995-1 |
| spellingShingle | Min-Ji Cho Hong-Gyun Lee Jae-Won Yoon Gil-Ran Kim Ja-Hyun Koo Reshma Taneja Brian T. Edelson You Jeong Lee Je-Min Choi Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis Experimental and Molecular Medicine |
| title | Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis |
| title_full | Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis |
| title_fullStr | Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis |
| title_full_unstemmed | Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis |
| title_short | Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis |
| title_sort | steady state memory phenotype conventional cd4 t cells exacerbate autoimmune neuroinflammation in a bystander manner via the bhlhe40 gm csf axis |
| url | https://doi.org/10.1038/s12276-023-00995-1 |
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