SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity
Abstract Background Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02594-9 |
| _version_ | 1797996102059819008 |
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| author | Patrick O’Connell Maja K. Blake Sarah Godbehere Andrea Amalfitano Yasser A. Aldhamen |
| author_facet | Patrick O’Connell Maja K. Blake Sarah Godbehere Andrea Amalfitano Yasser A. Aldhamen |
| author_sort | Patrick O’Connell |
| collection | DOAJ |
| description | Abstract Background Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7. Methods We subjected WT and SLAMF7−/− mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7−/− B cells into B cell-deficient mice (μMT) were also performed. Finally, B–T cell co-culture studies were performed, and a comparative cell–cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7− human CSF immune cells was constructed. Results We found SLAMF7−/− mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7−/− mice during EAE, and functional co-culture studies determined that SLAMF7−/− B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7−/− mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell–cell communication between SLAMF7-expressing cells. Conclusions Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS. |
| first_indexed | 2024-04-11T10:12:09Z |
| format | Article |
| id | doaj.art-c1243fae00384f15ace6980e927d20ed |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T10:12:09Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c1243fae00384f15ace6980e927d20ed2022-12-22T04:30:04ZengBMCJournal of Neuroinflammation1742-20942022-10-0119111810.1186/s12974-022-02594-9SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunityPatrick O’Connell0Maja K. Blake1Sarah Godbehere2Andrea Amalfitano3Yasser A. Aldhamen4Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State UniversityDepartment of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State UniversityDepartment of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State UniversityDepartment of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State UniversityDepartment of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State UniversityAbstract Background Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7. Methods We subjected WT and SLAMF7−/− mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7−/− B cells into B cell-deficient mice (μMT) were also performed. Finally, B–T cell co-culture studies were performed, and a comparative cell–cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7− human CSF immune cells was constructed. Results We found SLAMF7−/− mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7−/− mice during EAE, and functional co-culture studies determined that SLAMF7−/− B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7−/− mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell–cell communication between SLAMF7-expressing cells. Conclusions Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS.https://doi.org/10.1186/s12974-022-02594-9SLAMF7CD319CRACCMultiple sclerosisB cellsNeuroinflammation |
| spellingShingle | Patrick O’Connell Maja K. Blake Sarah Godbehere Andrea Amalfitano Yasser A. Aldhamen SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity Journal of Neuroinflammation SLAMF7 CD319 CRACC Multiple sclerosis B cells Neuroinflammation |
| title | SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity |
| title_full | SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity |
| title_fullStr | SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity |
| title_full_unstemmed | SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity |
| title_short | SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity |
| title_sort | slamf7 modulates b cells and adaptive immunity to regulate susceptibility to cns autoimmunity |
| topic | SLAMF7 CD319 CRACC Multiple sclerosis B cells Neuroinflammation |
| url | https://doi.org/10.1186/s12974-022-02594-9 |
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