Cargando…

SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity

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, howeve...

Descripción completa

Detalles Bibliográficos
Autores principales: O’Connell, Patrick, Blake, Maja K., Godbehere, Sarah, Amalfitano, Andrea, Aldhamen, Yasser A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533612/
https://www.ncbi.nlm.nih.gov/pubmed/36199066
http://dx.doi.org/10.1186/s12974-022-02594-9
_version_ 1784802382085881856
author O’Connell, Patrick
Blake, Maja K.
Godbehere, Sarah
Amalfitano, Andrea
Aldhamen, Yasser A.
author_facet O’Connell, Patrick
Blake, Maja K.
Godbehere, Sarah
Amalfitano, Andrea
Aldhamen, Yasser A.
author_sort O’Connell, Patrick
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02594-9.
format Online
Article
Text
id pubmed-9533612
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-95336122022-10-06 SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity O’Connell, Patrick Blake, Maja K. Godbehere, Sarah Amalfitano, Andrea Aldhamen, Yasser A. J Neuroinflammation Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02594-9. BioMed Central 2022-10-03 /pmc/articles/PMC9533612/ /pubmed/36199066 http://dx.doi.org/10.1186/s12974-022-02594-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
O’Connell, Patrick
Blake, Maja K.
Godbehere, Sarah
Amalfitano, Andrea
Aldhamen, Yasser A.
SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity
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 Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533612/
https://www.ncbi.nlm.nih.gov/pubmed/36199066
http://dx.doi.org/10.1186/s12974-022-02594-9
work_keys_str_mv AT oconnellpatrick slamf7modulatesbcellsandadaptiveimmunitytoregulatesusceptibilitytocnsautoimmunity
AT blakemajak slamf7modulatesbcellsandadaptiveimmunitytoregulatesusceptibilitytocnsautoimmunity
AT godbeheresarah slamf7modulatesbcellsandadaptiveimmunitytoregulatesusceptibilitytocnsautoimmunity
AT amalfitanoandrea slamf7modulatesbcellsandadaptiveimmunitytoregulatesusceptibilitytocnsautoimmunity
AT aldhamenyassera slamf7modulatesbcellsandadaptiveimmunitytoregulatesusceptibilitytocnsautoimmunity