Increased T-cell Reactivity and Elevated Levels of CD8+ Memory T-cells in Alzheimer’s Disease-patients and T-cell Hyporeactivity in an Alzheimer’s Disease-mouse Model: Implications for Immunotherapy

Key Points A major part of CD8+ memory T cells expresses CD40L, the key molecule for T-cell–dependent help. CD40L-expressing CD8+ T cells resemble functional CD4+ helper T cells.

Download Full-text

Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Hepatology ◽

10.1002/hep.24807 ◽

2012 ◽

Vol 55 (4) ◽

pp. 1130-1138 ◽

Cited By ~ 59

Author(s):

Stephen M. Brindley ◽

Allison M. Lanham ◽

Frederick M. Karrer ◽

Rebecca M. Tucker ◽

Andrew P. Fontenot ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Biliary Atresia ◽

Cell Reactivity ◽

T Cell Reactivity

Download Full-text

Abeta-induced meningoencephalitis is IFN- -dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0506209103 ◽

2006 ◽

Vol 103 (13) ◽

pp. 5048-5053 ◽

Cited By ~ 97

Author(s):

A. Monsonego ◽

J. Imitola ◽

S. Petrovic ◽

V. Zota ◽

A. Nemirovsky ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

T Cell ◽

Mouse Model ◽

Model Of Alzheimer’S Disease

Download Full-text

The RIG-I Agonist 3pRNA Synergizes with Checkpoint Blockade in Cancer Immunotherapy

Blood ◽

10.1182/blood.v126.23.3436.3436 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3436-3436 ◽

Cited By ~ 1

Author(s):

Simon Heidegger ◽

Diana Kreppel ◽

Michael Bscheider ◽

Alexander Wintges ◽

Sarah Bek ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Immunity ◽

Conflicts Of Interest ◽

Cytotoxic T Cells ◽

Type I ◽

Therapeutic Success ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Systemic Antibiotics

Abstract Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 has been shown to enhance anti-tumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination protocol that combines selective engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4-blockade. We found that vaccination together with RIG-I ligation strongly synergized with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells and potent anti-tumor immunity. Cross-priming of cytotoxic T cells as well as anti-tumor immunity required the adapter protein MAVS and type I interferon (IFN) signaling and were mediated by dendritic cells. In addition, the benefit of the combined immunization with anti-CTLA-4 was reduced by systemic antibiotics pointing to the requisite of an intact commensal microbiota in this context. Together, our findings describe a novel combinatorial strategy that may form the basis for the design of new type I IFN-based regimens that enhance antigen-specific T cell reactivity against cancer. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

10.1101/2020.10.03.20206151 ◽

2020 ◽

Author(s):

Gennadi V. Glinsky

Keyword(s):

T Cells ◽

T Cell ◽

Herd Immunity ◽

Inverse Correlation ◽

Mortality Rates ◽

Virus Spread ◽

Cell Reactivity ◽

Cell Immunity ◽

Potential Impact ◽

T Cell Reactivity

AbstractSeveral recent studies identified SARS-CoV-2 reactive T cells in people without exposure to the virus. However, pathophysiological implications of these findings remain unknown. Here, the potential impact of pre-existing T cell reactivity against SARS-CoV-2 in uninfected individuals on markedly different COVID-19 mortality levels in different countries has been investigated. The inverse correlation is documented between the prevalence of pre-existing SARS-CoV-2 reactive T cells in people without exposure to the virus and COVID-19 mortality rates in different countries. In countries with similar levels of pre-existing SARS-CoV-2 cross-reactive T cells in uninfected individuals, differences in COVID-19 mortality appear linked with the extend and consistency of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing). Collectively, these observations support the model that the level of pre-existing SARS-CoV-2 reactive T cells is one of the important determinants of the innate herd immunity against COVID-19. Together with the consistent social measures directed to limit the virus spread, high levels of pre-existing SARS-CoV-2 reactive T cells appear significant determinants diminishing the COVID-19 mortality. Observations reported in this contribution should have significant impact on definitions of the herd immunity threshold required to effectively stop the pandemic in different countries across the globe.

Download Full-text

The central role of T-cell memory in Alzheimer’s disease vaccination

Ageing Research ◽

10.4081/ar.2010.e5 ◽

2010 ◽

Vol 1 (1) ◽

pp. 5

Author(s):

Brian Giunta ◽

Amanda Ruscin ◽

Jon Salemi ◽

Alan Wolfson ◽

Francisco Fernandez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

T Cell ◽

Animal Models ◽

The Elderly ◽

Active Immunization ◽

T Cell Subsets ◽

Neurocognitive Deficits ◽

Cell Reactivity

Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloid-beta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.

Download Full-text

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

Pharmaceutics ◽

10.3390/pharmaceutics12090880 ◽

2020 ◽

Vol 12 (9) ◽

pp. 880 ◽

Cited By ~ 2

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.

Download Full-text