scholarly journals Poly-γ-Glutamic Acid/Alum Adjuvanted pH1N1 Vaccine-Immunized Aged Mice Exhibit a Significant Increase In Vaccine Efficacy With a Decrease in Age-Associated CD8+ T Cell Proportion in Splenocytes

2021 ◽  
Author(s):  
Jihyun Yang ◽  
Jaemoo Kim ◽  
Chaewon Kwak ◽  
Haryoung Poo
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Vaccine Efficacy ◽  
Cell Activation ◽  
The Elderly ◽  
Virus Challenge ◽  
Aged Mice ◽  
Flu Vaccine ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract BackgroundHighly contagious respiratory diseases caused by viral infections are a constantly emerging threat, particularly the elderly with the higher risk of developing serious complications. Vaccines are the best strategy for protection against influenza-related diseases. However, the elderly has lower vaccine efficacy and the age-driven decline of the influenza vaccine efficacy remains unresolved. In this study, we investigates the effect of an adjuvant, poly-γ-glutamic acid and alum (PGA/Alum) on vaccine efficacy in aged mice (18-months) and its mechanism is studied using ovalbumin as a model antigen and a commercial pandemic H1N1 flu vaccine. Antigen trafficking, dendritic cell (DC) activation, and the DC-mediated T cell activation were analyzed via in vivo imaging and flow cytometry. Antigen-specific humoral and cellular immune responses were evaluated in sera and splenocytes from the vaccinated mice. Also, we analyzed gene expression profiles of splenocytes of vaccinated mice via single-cell transcriptome sequencing and evaluated the protective efficacy against pH1N1 virus challenge.ResultsAged mice had low antigen trafficking and DC activation than younger mice (6-weeks), which was ameliorated by PGA/Alum with increased antigen uptake and DC activation leading to improved antigen-specific IFN-γ+CD8+ T lymphocyte frequencies higher in the vaccinated aged mice, to a similar extent as PGA/Alum adjuvanted vaccine-immunized young mice. The results of single-cell transcriptome sequencing display that PGA/Alum also reduced the proportion of age-associated CD8+ T cell subsets and gene levels of inhibitory regulators in CD8+ T cells, which may play a role in the recovery of CD8+ T cell activation. Finally, PGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice were completely protected (100% survival) compared to aged mice immunized with vaccine only (0% survival) after pH1N1 virus challenge, akin to the efficacy of the vaccinated young mice (100% survival).ConclusionsPGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice showed a significant increase in vaccine efficacy compared to aged mice administered with vaccine only. The enhanced vaccine efficacy by PGA/Alum is associated with significant increases activation of DCs and effector CD8+ T cells and a decrease in age-associated CD8+ T cell proportion of splenocytes. Collectively, PGA/Alum adjuvanted flu vaccine may be a promising vaccine candidate for the elderly.

Multiple CD4 and CD8 T-cell activation parameters predict vaccine efficacy in vivo mediated by individual DC-activating agonists

Vaccine ◽  
2007 ◽  
Vol 25 (8) ◽  
pp. 1379-1389 ◽  
Author(s):  
Marij J.P. Welters ◽  
Martijn S. Bijker ◽  
Susan J.F. van den Eeden ◽  
Kees L.M.C. Franken ◽  
Cornelis J.M. Melief ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Vaccine Efficacy ◽  
Cell Activation ◽  
Activation Parameters ◽  
Cd8 T Cell

Thymopoiesis, Alterations in Dendritic cells and Tregs and Reduced T-Cell Activation in Successful Extracorporeal Photopheresis Treatment of GVHD

2021 ◽  
Author(s):  
Aisling M Flinn ◽  
Anna Ehrlich ◽  
Catherine Roberts ◽  
Xiao Nong Wang ◽  
Janet Chou ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Transcriptional Level ◽  
Cell Transplant ◽  
Extracorporeal Photopheresis ◽  
Hematopoietic Stem ◽  
Cell Transcriptome ◽  
The Impact

Abstract Acute graft-versus-host disease (aGVHD) is a significant complication of allogeneic hematopoietic stem cell transplant (HSCT) and negatively affects T-cell reconstitution. Extracorporeal photopheresis (ECP) reduces aGVHD, but the mechanisms remain incompletely understood. Our objective was to examine the impact of ECP on thymopoiesis in pediatric aGVHD and the mechanisms at a cellular and transcriptional level. Sixteen pediatric HSCT patients were recruited; 6 with ECP-treated aGVHD, 5 without aGVHD and 5 with aGVHD treated with corticosteroids only. Thymopoiesis was evaluated by measuring naive T-cells, TRECs, IL-7 and T-cell receptor repertoire diversity. Regulatory T-cell (Treg) enumeration and function and dendritic cell (DC) enumeration and phenotype were analyzed using flow cytometry. T-cell transcriptome analysis was performed on ECP patients after treatment and responders pre and post-treatment. Four ECP-responders demonstrated thymic-dependent T-cell recovery, and superior median naïve T-cell numbers at 8 and 12 months post-HSCT compared to the aGVHD corticosteroid group. Increased Tregs and Treg suppressive function, reduced cDC/pDC and DC co-stimulatory marker expression in ECP responders suggest upregulated peripheral tolerance, findings not observed in partial responders. Responder post-ECP CD3+ T-cell transcriptional profile demonstrated 3333 downregulated and 364 upregulated genes, with significant downregulation of ERRα and GαS pathways, and reduced expression of pro-inflammatory and adhesion proteins. Thymic function improves with successful ECP treatment. ECP reduces T-cell activation and impacts peripheral tolerance via DCs and Tregs. Differences in thymic recovery, DC and Treg cellular patterns and the T-cell transcriptome were observed between ECP responders and partial responders and require further validation and investigation in additional patients.

T cell activation in the elderly: Evidence for specific deficiencies in T cell/accessory cell interactions

1990 ◽  
Vol 51 (3) ◽  
pp. 265-276 ◽  
Author(s):  
Ian Beckman ◽  
Katina Dimopoulos ◽  
Xu Xiaoning ◽  
John Bradley ◽  
Philip Henschke ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
The Elderly ◽  
Cell Interactions ◽  
Accessory Cell

scholarly journals Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Kristin L. Griffiths ◽  
Mushtaq Ahmed ◽  
Shibali Das ◽  
Radha Gopal ◽  
William Horne ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Vaccine Efficacy ◽  
Cell Activation

scholarly journals Thymopoiesis, Alterations in Dendritic Cells and Tregs, and Reduced T Cell Activation in Successful Extracorporeal Photopheresis Treatment of GVHD

2021 ◽  
Author(s):  
Aisling M. Flinn ◽  
Anna Ehrlich ◽  
Catherine Roberts ◽  
Xiao Nong Wang ◽  
Janet Chou ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Transcriptional Level ◽  
Cell Transplant ◽  
Extracorporeal Photopheresis ◽  
Hematopoietic Stem ◽  
Cell Transcriptome ◽  
The Impact

AbstractAcute graft-versus-host disease (aGVHD) is a significant complication of allogeneic hematopoietic stem cell transplant (HSCT) and negatively affects T cell reconstitution. Extracorporeal photopheresis (ECP) reduces aGVHD, but the mechanisms remain incompletely understood. Our objective was to examine the impact of ECP on thymopoiesis in pediatric aGVHD and the mechanisms at a cellular and transcriptional level. Sixteen pediatric HSCT patients were recruited: 6 with ECP-treated aGVHD, 5 without aGVHD, and 5 with aGVHD treated with corticosteroids only. Thymopoiesis was evaluated by measuring naive T cells, TRECs, IL-7, and T cell receptor repertoire diversity. Regulatory T cell (Treg) enumeration and function and dendritic cell (DC) enumeration and phenotype were analyzed using flow cytometry. T cell transcriptome analysis was performed on ECP patients after treatment and responders pre- and post-treatment. Four ECP responders demonstrated thymic-dependent T cell recovery, and superior median naïve T cell numbers at 8 and 12 months post-HSCT compared to the aGVHD corticosteroid group. Increased Tregs and Treg suppressive function, reduced cDC/pDC and DC co-stimulatory marker expression in ECP responders suggest upregulated peripheral tolerance; these findings were not observed in partial responders. Responder post-ECP CD3+ T cell transcriptional profile demonstrated 3333 downregulated and 364 upregulated genes, with significant downregulation of ERRα and GαS pathways, and reduced expression of pro-inflammatory and adhesion proteins.Thymic function improves with successful ECP treatment. ECP reduces T cell activation and impacts peripheral tolerance via DCs and Tregs. Differences in thymic recovery, DC, and Treg cellular patterns and the T cell transcriptome were observed between ECP responders and partial responders and require further validation and investigation in additional patients.

scholarly journals Onchocerciasis Fingerprints in the Geriatric Population: Does Host Immunity Play a Role?

2021 ◽  
Vol 6 (3) ◽  
pp. 153
Author(s):  
Cabirou Mounchili Shintouo ◽  
Robert Adamu Shey ◽  
Tony Mets ◽  
Luc Vanhamme ◽  
Jacob Souopgui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Immune Dysfunction ◽  
The Elderly ◽  
Geriatric Population ◽  
Lymphatic Complications

One of the most debilitating consequences of aging is the progressive decline in immune function, known as immunosenescence. This phenomenon is characterized by a shift in T-cell phenotypes, with a manifest decrease of naive T-cells—dealing with newly encountered antigens—and a concomitant accumulation of senescent and regulatory T-cells, leading to a greater risk of morbidity and mortality in older subjects. Additionally, with aging, several studies have unequivocally revealed an increase in the prevalence of onchocerciasis infection. Most lymphatic complications, skin and eye lesions due to onchocerciasis are more frequent among the elderly population. While the reasons for increased susceptibility to onchocerciasis with age are likely to be multi-factorial, age-associated immune dysfunction could play a key role in the onset and progression of the disease. On the other hand, there is a growing consensus that infection with onchocerciasis may evoke deleterious effects on the host’s immunity and exacerbate immune dysfunction. Indeed, Onchocerca volvulus has been reported to counteract the immune responses of the host through molecular mimicry by impairing T-cell activation and interfering with the processing of antigens. Moreover, reports indicate impaired cellular and humoral immune responses even to non-parasite antigens in onchocerciasis patients. This diminished protective response may intensify the immunosenescence outcomes, with a consequent vulnerability of those affected to additional diseases. Taken together, this review is aimed at contributing to a better understanding of the immunological and potential pathological mechanisms of onchocerciasis in the older population.

scholarly journals Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

2018 ◽  
Vol 115 (52) ◽  
pp. 13347-13352 ◽  
Author(s):  
Noga Ron-Harel ◽  
Giulia Notarangelo ◽  
Jonathan M. Ghergurovich ◽  
Joao A. Paulo ◽  
Peter T. Sage ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Carbon Metabolism ◽  
Cell Activation ◽  
Aged Mice ◽  
Naïve T Cells ◽  
One Carbon Metabolism ◽  
Naïve T Cell ◽  
Naive T Cell

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

scholarly journals Hiding in Plain Sight: Virtually Unrecognizable Memory Phenotype CD8+ T cells

2020 ◽  
Vol 21 (22) ◽  
pp. 8626
Author(s):  
Daniel Thiele ◽  
Nicole L. La Gruta ◽  
Angela Nguyen ◽  
Tabinda Hussain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Recent Literature ◽  
Biological Significance ◽  
Cell Lineage ◽  
The Elderly ◽  
Specific Response

Virtual memory T (TVM) cells are a recently described population of conventional CD8+ T cells that, in spite of their antigen inexperience, express markers of T cell activation. TVM cells exhibit rapid responsiveness to both antigen-specific and innate stimuli in youth but acquire intrinsic antigen-specific response defects in the elderly. In this article, we review how the identification of TVM cells necessitates a re-evaluation of accepted paradigms for conventional memory T (TMEM) cells, the potential for heterogeneity within the TVM population, and the defining characteristics of TVM cells. Further, we highlight recent literature documenting the development of TVM cells as a distinct CD8+ T cell lineage as well their biological significance in the context of disease.

scholarly journals The GSK3β-β-catenin-TCF1 pathway improves naive T cell activation in old adults by upregulating miR-181a

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhongde Ye ◽  
Timothy M. Gould ◽  
Huimin Zhang ◽  
Jun Jin ◽  
Cornelia M. Weyand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
The Elderly ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers ◽  
Old Adults ◽  
Tcr Activation

AbstractMicroRNAs play an important role in the regulation of T cell development, activation, and differentiation. One of the most abundant microRNAs in lymphocytes is miR-181a, which controls T cell receptor (TCR) activation thresholds in thymic selection as well as in peripheral T cell responses. We previously found that miR-181a levels decline in T cells in the elderly. In this study, we identified TCF1 as a transcriptional regulator of pri-miR-181a. A decline in TCF1 levels in old individuals accounted for the reduced miR-181a expression impairing TCR signaling. Inhibition of GSK3ß restored expression of miR-181a by inducing TCF1 in T cells from old adults. GSK3ß inhibition enhanced TCR signaling to increase downstream expression of activation markers and production of IL-2. The effect involved the upregulation of miR-181a and the inhibition of DUSP6 expression. Thus, inhibition of GSK3ß can restore responses of old T cells by inducing miR-181a expression through TCF1.

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