Biology subjects

Lutz, S. E.

Publications and source records attributed to Lutz, S. E..

3 recordsLinked to original sources

bioRxiv2022

Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier

CXCL10 is an interferon-inducible chemokine that can recruit CXCR3+ leukocytes to the central nervous system, leading to neuroinflammation, demyelination, and neuronal losses. How CXCL10 promotes leukocyte extravasation and diapedesis across the blood-brain barrier - formed by brain endothelial cells - is poorly understood. Here, we report that CXCL10 mediates CD4+ T cell migration through the brain endothelial cell cytoplasm (transcellular), but not cell-cell junctions (paracellular), via the vesicular trafficking protein Caveolin-1. Caveolin-1 promotes CXCL10 aggregation into cytoplasmic stores in brain endothelial cells in vitro to provide the local, high concentration necessary for recruitment of CXCR3+ leukocytes. This process also requires LFA-1 activity. In the absence of Caveolin-1, endothelial CXCL10 is secreted, and the local signaling cues are lost. Consistent with our in vitro data, genetic ablation of Caveolin-1 in endothelial cells reduces the severity of active experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis, by decreasing the infiltration of CXCR3+ T cells into the CNS. Moreover, loss of Caveolin-1 protects against the adoptive transfer of autoreactive T cells. Our findings establish a novel mechanism by which brain endothelial cells utilize Caveolin-1 dependent CXCL10 intracellular stores to license T cells for transcellular migration across the blood-brain barrier.

immunology↗

bioRxiv2022

Commensal-specific CD4 T cells promote inflammation in the central nervous system via molecular mimicry

Commensal bacteria are critical regulators of both tissue homeostasis and the development and exacerbation of autoimmunity. However, it remains unclear how the intestinal microbiota contributes to inflammation in tissues such as the central nervous system (CNS) where these microbes are typically absent and whether T cell receptor (TCR) specificity for commensal-derived antigens is important to the development of tissue inflammation-related outcomes. Here, we found that ileum- and cecum-colonizing segmented filamentous bacteria (SFB)-specific T cells (clone TCR7B8) can infiltrate the CNS wherein they can be reactivated and produce high levels of inflammatory cytokines including IFN{gamma}, IL-17A, TNF, and GM-CSF in the absence of regulatory T cells. In contrast, other SFB-specific T cells (clone TCR1A2) recognizing an epitope in which 8/9 amino acids overlap with those recognized by TCR7B8 failed to induce such neuroinflammation. Despite their similar SFB-derived peptide antigen targets, TCR7B8 was found to recognize peptides derived from host proteins including receptor tyrosine-protein kinase ErbB2, trophinin 1, and anaphase-promoting complex subunit 2 in vitro, whereas TCR1A2 did not, indicating that TCR7B8 induces CNS inflammation via molecular mimicry. Immune checkpoint blockade accelerated TCR7B8-mediated CNS inflammation, suggesting a potential cause of immune-related adverse events induced in cancer patients undergoing such treatment. Together, our findings reveal a potential mechanism whereby gut commensal-specific T cells are dysregulated and contribute to extraintestinal inflammation.

immunology↗

bioRxiv2022

Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating vascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by SARS-CoV-2 in vivo. This analysis revealed significant suppression of Wnt/{beta}-catenin signaling, a critical regulator of blood brain barrier integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/{beta}-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected blood brain barrier integrity, reduced T cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this therapeutic strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/{beta}-catenin signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following acute viral infections.

neuroscience↗