Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation
Abstract The endothelial blood-brain barrier (BBB) tightly controls T cell entry into the central nervous system (CNS). T cell extravasation across the BBB involves a multi-step cascade with a predominant role of α4β1-integrins. In contrast to CD4 T cells, α4β1-integrin mediated CD8 T cell interacti...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-025-02021-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850107598396719104 |
|---|---|
| author | Javier Pareja Sidar Aydin Mara Zbinden Elisa Bouillet Niklas Zollinger Vidusiya Theivendram Amal Fahmi Petr Pleskač Sara Barcos Felix Paas Florencia Kloster Aida Muñoz Blázquez Nicolas Fonta Doron Merkler Urban Deutsch Britta Engelhardt |
| author_facet | Javier Pareja Sidar Aydin Mara Zbinden Elisa Bouillet Niklas Zollinger Vidusiya Theivendram Amal Fahmi Petr Pleskač Sara Barcos Felix Paas Florencia Kloster Aida Muñoz Blázquez Nicolas Fonta Doron Merkler Urban Deutsch Britta Engelhardt |
| author_sort | Javier Pareja |
| collection | DOAJ |
| description | Abstract The endothelial blood-brain barrier (BBB) tightly controls T cell entry into the central nervous system (CNS). T cell extravasation across the BBB involves a multi-step cascade with a predominant role of α4β1-integrins. In contrast to CD4 T cells, α4β1-integrin mediated CD8 T cell interaction with the BBB was proposed to involve the tight junction protein junctional adhesion molecule (JAM)-B. Here, we made use of ODC-OVA mice expressing ovalbumin as neo-self-antigen in oligodendrocytes that is solely visible to CD8 T cells, allowing to investigate CD8 T cell-mediated autoimmune neuroinflammation. We generated JAM-B-deficient ODC-OVA mice (ODC-OVA; JAM-BKO mice) and compared CD8 T cell mediated autoimmune neuroinflammation to their ODC-OVA; JAM-BWT littermates. ODC-OVA; JAM-BKO mice developed ameliorated clinical disease, which was associated with a marked reduction in CD8 T cell infiltration into the CNS parenchyma. Surprisingly, lack of JAM-B did not affect CD8 T cell arrest or extravasation in spinal cord microvessels but rather resulted in CD8 T cell accumulation in the subarachnoid space and perivascular spaces in ODC-OVA; JAM-BKO mice. Detection of Jam-2 RNA expression in cells other than BBB endothelial cells contributing to CNS barriers including astrocytes forming the glia limitans, Bergmann glial cells, meningeal fibroblasts and choroid plexus epithelial cells suggests that JAM-B may regulate CD8 T cell entry into the CNS at barriers other than the BBB, particularly at the glia limitans. Thus, targeting JAM-B could provide a therapeutic strategy for treating neuroinflammation without disrupting T cell-mediated immune surveillance in CNS border compartments. |
| format | Article |
| id | doaj-art-9f98bd3d02944577b58744e110c745fa |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-9f98bd3d02944577b58744e110c745fa2025-08-20T02:38:32ZengBMCActa Neuropathologica Communications2051-59602025-05-0113112310.1186/s40478-025-02021-zLack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammationJavier Pareja0Sidar Aydin1Mara Zbinden2Elisa Bouillet3Niklas Zollinger4Vidusiya Theivendram5Amal Fahmi6Petr Pleskač7Sara Barcos8Felix Paas9Florencia Kloster10Aida Muñoz Blázquez11Nicolas Fonta12Doron Merkler13Urban Deutsch14Britta Engelhardt15Theodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernDepartment of Pathology and Immunology, Division of Clinical Pathology, University and University Hospitals of GenevaDepartment of Pathology and Immunology, Division of Clinical Pathology, University and University Hospitals of GenevaTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernAbstract The endothelial blood-brain barrier (BBB) tightly controls T cell entry into the central nervous system (CNS). T cell extravasation across the BBB involves a multi-step cascade with a predominant role of α4β1-integrins. In contrast to CD4 T cells, α4β1-integrin mediated CD8 T cell interaction with the BBB was proposed to involve the tight junction protein junctional adhesion molecule (JAM)-B. Here, we made use of ODC-OVA mice expressing ovalbumin as neo-self-antigen in oligodendrocytes that is solely visible to CD8 T cells, allowing to investigate CD8 T cell-mediated autoimmune neuroinflammation. We generated JAM-B-deficient ODC-OVA mice (ODC-OVA; JAM-BKO mice) and compared CD8 T cell mediated autoimmune neuroinflammation to their ODC-OVA; JAM-BWT littermates. ODC-OVA; JAM-BKO mice developed ameliorated clinical disease, which was associated with a marked reduction in CD8 T cell infiltration into the CNS parenchyma. Surprisingly, lack of JAM-B did not affect CD8 T cell arrest or extravasation in spinal cord microvessels but rather resulted in CD8 T cell accumulation in the subarachnoid space and perivascular spaces in ODC-OVA; JAM-BKO mice. Detection of Jam-2 RNA expression in cells other than BBB endothelial cells contributing to CNS barriers including astrocytes forming the glia limitans, Bergmann glial cells, meningeal fibroblasts and choroid plexus epithelial cells suggests that JAM-B may regulate CD8 T cell entry into the CNS at barriers other than the BBB, particularly at the glia limitans. Thus, targeting JAM-B could provide a therapeutic strategy for treating neuroinflammation without disrupting T cell-mediated immune surveillance in CNS border compartments.https://doi.org/10.1186/s40478-025-02021-zCD8 T cellCNSBBBJAM-BGlia limitansNeuroinflammation |
| spellingShingle | Javier Pareja Sidar Aydin Mara Zbinden Elisa Bouillet Niklas Zollinger Vidusiya Theivendram Amal Fahmi Petr Pleskač Sara Barcos Felix Paas Florencia Kloster Aida Muñoz Blázquez Nicolas Fonta Doron Merkler Urban Deutsch Britta Engelhardt Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation Acta Neuropathologica Communications CD8 T cell CNS BBB JAM-B Glia limitans Neuroinflammation |
| title | Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation |
| title_full | Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation |
| title_fullStr | Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation |
| title_full_unstemmed | Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation |
| title_short | Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation |
| title_sort | lack of junctional adhesion molecule jam b traps cd8 t cells in cns border zones and ameliorates autoimmune neuroinflammation |
| topic | CD8 T cell CNS BBB JAM-B Glia limitans Neuroinflammation |
| url | https://doi.org/10.1186/s40478-025-02021-z |
| work_keys_str_mv | AT javierpareja lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT sidaraydin lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT marazbinden lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT elisabouillet lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT niklaszollinger lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT vidusiyatheivendram lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT amalfahmi lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT petrpleskac lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT sarabarcos lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT felixpaas lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT florenciakloster lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT aidamunozblazquez lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT nicolasfonta lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT doronmerkler lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT urbandeutsch lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation AT brittaengelhardt lackofjunctionaladhesionmoleculejambtrapscd8tcellsincnsborderzonesandamelioratesautoimmuneneuroinflammation |