scholarly journals CD4+ effector T cells accelerate Alzheimer’s disease in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jatin Machhi ◽  
Pravin Yeapuri ◽  
Yaman Lu ◽  
Emma Foster ◽  
Rupesh Chikhale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Amyloid Beta ◽  
Cell Epitope ◽  
Effector T Cells ◽  
Microglia Activation ◽  
Chimeric Mouse ◽  
Antigen Specificity

Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical Abstract

scholarly journals Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 880 ◽  
Author(s):  
Norwin Kubick ◽  
Patrick C. Henckell Flournoy ◽  
Ana-Maria Enciu ◽  
Gina Manda ◽  
Michel-Edwar Mickael
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Subpopulation ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Endothelial Integrity

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.

The T cell response to amyloid-beta to mitochondrial antigens in Alzheimer's disease

2000 ◽  
Vol 21 ◽  
pp. 234
Author(s):  
Marco Salvetti ◽  
Giovanni Ristori ◽  
Stefania Cannoni ◽  
Paolo Tisei ◽  
Alessia Perna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cell ◽  
Amyloid Beta ◽  
Cell Response ◽  
T Cell Response ◽  
Mitochondrial Antigens

scholarly journals Prototype Alzheimer’s Disease Vaccine Using the Immunodominant B Cell Epitope from β-Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide

2005 ◽  
Vol 174 (3) ◽  
pp. 1580-1586 ◽  
Author(s):  
Michael G. Agadjanyan ◽  
Anahit Ghochikyan ◽  
Irina Petrushina ◽  
Vitaly Vasilevko ◽  
Nina Movsesyan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
Binding Peptide ◽  
Hla Dr ◽  
B Cell Epitope ◽  
Β Amyloid

scholarly journals Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease

2021 ◽  
Author(s):  
Dallin Dressman ◽  
Thomas Buttrick ◽  
Maria Cimpean ◽  
David Bennett ◽  
Vilas Menon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Rna Sequencing ◽  
Disease Risk ◽  
Synaptic Function ◽  
T Cell Subsets ◽  
Age Related

Recent studies identifying expression quantitative trait loci (eQTL) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells, and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched healthy controls from the Religious Orders Study/Memory and Aging Project. Correlating gene expression data with AD neuropathological traits, and with single nucleotide polymorphisms (SNPs) to detect eQTLs, we identified several significant genes involved in T cell senescence and cytotoxicity, consistent with T cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Overall, our data sheds more light on the genetic basis behind phenotypic changes in T cells during aging and AD.

scholarly journals Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations

2021 ◽  
Vol 17 (7) ◽  
pp. e1009709
Author(s):  
Bonnie Douglas ◽  
Yun Wei ◽  
Xinshe Li ◽  
Annabel Ferguson ◽  
Li-Yin Hung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Transgenic Line ◽  
Fluorescent Protein ◽  
Cell Epitope ◽  
Cd4 T Cell ◽  
Cell Phenotype ◽  
T Cell Epitope ◽  
Antigen Specificity

Helminths are distinct from microbial pathogens in both size and complexity, and are the likely evolutionary driving force for type 2 immunity. CD4+ helper T cells can both coordinate worm clearance and prevent immunopathology, but issues of T cell antigen specificity in the context of helminth-induced Th2 and T regulatory cell (Treg) responses have not been addressed. Herein, we generated a novel transgenic line of the gastrointestinal nematode Strongyloides ratti expressing the immunodominant CD4+ T cell epitope 2W1S as a fusion protein with green fluorescent protein (GFP) and FLAG peptide in order to track and study helminth-specific CD4+ T cells. C57BL/6 mice infected with this stable transgenic line (termed Hulk) underwent a dose-dependent expansion of activated CD44hiCD11ahi 2W1S-specific CD4+ T cells, preferentially in the lung parenchyma. Transcriptional profiling of 2W1S-specific CD4+ T cells isolated from mice infected with either Hulk or the enteric bacterial pathogen Salmonella expressing 2W1S revealed that pathogen context exerted a dominant influence over CD4+ T cell phenotype. Interestingly, Hulk-elicited 2W1S-specific CD4+ T cells exhibited both Th2 and Treg phenotypes and expressed high levels of the EGFR ligand amphiregulin, which differed greatly from the phenotype of 2W1S-specific CD4+ T cells elicited by 2W1S-expressing Salmonella. While immunization with 2W1S peptide did not enhance clearance of Hulk infection, immunization did increase total amphiregulin production as well as the number of amphiregulin-expressing CD3+ cells in the lung following Hulk infection. Altogether, this new model system elucidates effector as well as immunosuppressive and wound reparative roles of helminth-specific CD4+ T cells. This report establishes a new resource for studying the nature and function of helminth-specific T cells.

scholarly journals Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Alireza Faridar ◽  
Aaron D Thome ◽  
Weihua Zhao ◽  
Jason R Thonhoff ◽  
David R Beers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
T Cell Proliferation ◽  
Inflammatory Macrophages

Abstract Inflammation is a significant component of Alzheimer’s disease pathology. While neuroprotective microglia are important for containment/clearance of Amyloid plaques and maintaining neuronal survival, Alzheimer inflammatory microglia may play a detrimental role by eliciting tau pathogenesis and accelerating neurotoxicity. Regulatory T cells have been shown to suppress microglia-mediated inflammation. However, the role of regulatory T cells in ameliorating the proinflammatory immune response in Alzheimer’s disease requires further investigation. Forty-six patients with Alzheimer disease, 42 with mild cognitive impairment and 41 healthy controls were studied. The phenotypes of peripheral regulatory T cells were assessed with multicolour flow cytometry. Regulatory T cells were co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell-derived pro-inflammatory macrophages and changes in interleukin-6/tumour necrosis-alpha transcripts and protein levels were measured. Freshly isolated regulatory T cells were expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin-2 and rapamycin to promote their suppressive function. We found that the suppressive function of regulatory T cells on responder T-cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. CD25 mean fluorescence intensity in regulatory T-cell population was also reduced in Alzheimer dementia patients. Regulatory T cells did not suppress pro-inflammatory macrophages at baseline. Following ex vivo expansion, regulatory T-cell suppression of responder T-cell proliferation and pro-inflammatory macrophage activation increased in both patients and controls. Expanded regulatory T cells exerted their immunoregulatory function on pro-inflammatory macrophages through a contact-mediated mechanism. In conclusion, regulatory T-cell immunophenotype and function are compromised in Alzheimer’s disease. Following ex vivo expansion, the immunomodulatory function of regulatory T cells is enhanced even at advanced stages of Alzheimer’s disease. Restoration of regulatory T-cell function could be explored as a means to modulate the inflammatory status of Alzheimer’s disease.

scholarly journals Administration of anti-ERMAP antibody ameliorates Alzheimer’s disease in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Haiyan Liu ◽  
Jin Zhao ◽  
Yujun Lin ◽  
Min Su ◽  
Laijun Lai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Cognitive Performance ◽  
Neurodegenerative Disorder ◽  
Age Related ◽  
Macrophage Phagocytosis ◽  
B7 Family ◽  
The Brain

Abstract Background Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. Methods We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice. Results  We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aβ in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aβ plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the macrophage phagocytosis of Aβ are enhanced in the anti-ERMAP mAb-treated AD mice. Conclusions Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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