Do peripheral protein oligomers in neurodegenerative diseases shape T cell responses beyond the brain?

Annabelle Ferguson; Simon Milling

doi:10.1111/imm.13414

21. Environmental conditions perceived by the brain alter CD4 T cell responses through an adiponectin-dependent mechanism

Brain Behavior and Immunity ◽

10.1016/j.bbi.2013.07.033 ◽

2013 ◽

Vol 32 ◽

pp. e6-e7

Author(s):

N. Glaichenhaus ◽

M. Canali ◽

J. Soria ◽

E. Murris ◽

J. Chabry ◽

...

Keyword(s):

T Cell ◽

Environmental Conditions ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses ◽

The Brain ◽

Dependent Mechanism

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IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

10.1101/418665 ◽

2018 ◽

Author(s):

Carleigh A. O’Brien ◽

Samantha J. Batista ◽

Katherine M. Still ◽

Tajie H. Harris

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Chronic Phase ◽

T Cell Responses ◽

T Cell Response ◽

Neutrophil Recruitment ◽

Cns Infection ◽

Cell Responses ◽

The Brain

AbstractControl of chronic CNS infection with the parasiteToxoplasma gondiirequires an ongoing T cell response in the brain. Immunosuppressive cytokines are also important for preventing lethal immunopathology during chronic infection. To explore the loss of suppressive cytokine exclusively during the chronic phase of infection we blocked IL-10 receptor (IL-10R). Blockade was associated with widespread changes in the inflammatory response, including increased antigen presenting cell (APC) activation, expansion of CD4+ T cells, and increased neutrophil recruitment to the brain, consistent with previous reports. We then sought to identify regulatory mechanisms contributing to IL-10 production, focusing on ICOS (inducible T cell costimulator), a molecule that promotes IL-10 production in many systems. Unexpectedly, ICOS-ligand (ICOSL) blockade led to a local expansion of effector T cells in the inflamed brain without affecting IL-10 production or APC activation. Instead, we found that ICOSL blockade led to changes in T cells associated with their proliferation and survival. Specifically, we observed increased expression of IL-2 associated signaling molecules, including CD25, STAT5 phosphorylation, Ki67, and Bcl-2 in T cells in the brain. Interestingly, increases in CD25 and Bcl-2 were not observed following IL-10R blockade. Also unlike IL-10R blockade, ICOSL blockade led to an expansion of both CD8+ and CD4+ T cells in the brain, with no expansion of peripheral T cell populations or neutrophil recruitment to the brain Overall, these results suggest that IL-10 and ICOS differentially regulate T cell responses in the brain during chronicT. gondiiinfection.

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154 Interferon-gamma prevents death of bystander neurons during CD8 T-cell responses in the brain

Cytokine ◽

10.1016/j.cyto.2008.07.197 ◽

2008 ◽

Vol 43 (3) ◽

pp. 272

Author(s):

Kirsten Richter ◽

Jürgen Hausmann ◽

Peter Staeheli

Keyword(s):

T Cell ◽

Interferon Gamma ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

The Brain

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IL-22 hinders antiviral T cell responses and exacerbates neurological disorders in ZIKV-infected immunocompetent neonatal mice

10.21203/rs.3.rs-31941/v1 ◽

2020 ◽

Author(s):

Yuejin Liang ◽

Panpan Yi ◽

Wenjuan Ru ◽

Zuliang Jie ◽

Hui Wang ◽

...

Keyword(s):

Weight Loss ◽

T Cell ◽

Neurological Disorders ◽

T Cell Responses ◽

Host Immunity ◽

Zikv Infection ◽

Cell Responses ◽

The Brain

Abstract Background The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is unknown. Methods The cellular source of IL-22 was identified in IFNAR−/− mice and WT neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old wild-type (WT) and IL-22−/− mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, we infected mouse primary astrocytes in vitro, and characterized the reactive astrocyte phenotype. Human glial cell line was also infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression and viral loads. Results We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 days post-infection (dpi), and ultimately succumbed to infection at 16–19 dpi. Surprisingly, IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. ZIKV infection facilitated a neurotoxic polarization of A1-prone astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a marginal effect on glial cells in vitro, IL-22−/− mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain. Conclusions Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

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Interferon-γ Prevents Death of Bystander Neurons during CD8 T Cell Responses in the Brain

American Journal Of Pathology ◽

10.2353/ajpath.2009.080897 ◽

2009 ◽

Vol 174 (5) ◽

pp. 1799-1807 ◽

Cited By ~ 13

Author(s):

Kirsten Richter ◽

Jürgen Hausmann ◽

Peter Staeheli

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Interferon Γ ◽

Cell Responses ◽

The Brain

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CARD9 Deficiency Increases Hippocampal Injury Following Acute Neurotropic Picornavirus Infection but Does Not Affect Pathogen Elimination

International Journal of Molecular Sciences ◽

10.3390/ijms22136982 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6982

Author(s):

Suvarin Pavasutthipaisit ◽

Melanie Stoff ◽

Tim Ebbecke ◽

Malgorzata Ciurkiewicz ◽

Sabine Mayer-Lambertz ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Virus Infection ◽

T Cell Responses ◽

Neurotropic Virus ◽

Genetic Ablation ◽

Cell Responses ◽

Neuronal Precursor Cells ◽

The Impact ◽

The Brain

Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9−/− and corresponding C57BL/6 wild-type control mice were infected with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9−/− mice showed an increased loss of neuronal nuclear protein+ mature neurons and doublecortin+ neuronal precursor cells and an increase in β-amyloid precursor protein+ damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8+ T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection.

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C-type lectin receptor DCIR contributes to hippocampal injury in acute neurotropic virus infection

Scientific Reports ◽

10.1038/s41598-021-03201-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Melanie Stoff ◽

Tim Ebbecke ◽

Malgorzata Ciurkiewicz ◽

Suvarin Pavasutthipaisit ◽

Sabine Mayer-Lambertz ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Interleukin 2 ◽

T Cell Responses ◽

Lectin Receptors ◽

Neurotropic Virus ◽

Cell Responses ◽

The Impact ◽

The Brain

AbstractNeurotropic viruses target the brain and contribute to neurologic diseases. C-type lectin receptors (CLRs) are pattern recognition receptors that recognize carbohydrate structures on endogenous molecules and pathogens. The myeloid CLR dendritic cell immunoreceptor (DCIR) is expressed by antigen presenting cells and mediates inhibitory intracellular signalling. To investigate the effect of DCIR on neurotropic virus infection, mice were infected experimentally with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue of TMEV-infected C57BL/6 mice and DCIR−/− mice were analysed by histology, immunohistochemistry and RT-qPCR, and spleen tissue by flow cytometry. To determine the impact of DCIR deficiency on T cell responses upon TMEV infection in vitro, antigen presentation assays were utilised. Genetic DCIR ablation in C57BL/6 mice was associated with an ameliorated hippocampal integrity together with reduced cerebral cytokine responses and reduced TMEV loads in the brain. Additionally, absence of DCIR favoured increased peripheral cytotoxic CD8+ T cell responses following TMEV infection. Co-culture experiments revealed that DCIR deficiency enhances the activation of antigen-specific CD8+ T cells by virus-exposed dendritic cells (DCs), indicated by increased release of interleukin-2 and interferon-γ. Results suggest that DCIR deficiency has a supportive influence on antiviral immune mechanisms, facilitating virus control in the brain and ameliorates neuropathology during acute neurotropic virus infection.

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Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria

Frontiers in Immunology ◽

10.3389/fimmu.2021.711876 ◽

2021 ◽

Vol 12 ◽

Author(s):

Johanna F. Scheunemann ◽

Julia J. Reichwald ◽

Patricia Jebett Korir ◽

Janina M. Kuehlwein ◽

Lea-Marie Jenster ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cerebral Malaria ◽

Plasmodium Berghei ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Type I ◽

Experimental Cerebral Malaria ◽

Cell Responses ◽

The Brain

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

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