scholarly journals Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ghada Alsaleh ◽  
Isabel Panse ◽  
Leo Swadling ◽  
Hanlin Zhang ◽  
Felix Clemens Richter ◽  
...  
Keyword(s):  
T Cells ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Immune Memory ◽  
Healthy Human ◽  
Vaccine Responses ◽  
Human T Cells ◽  
Human Volunteers ◽  
And Function ◽  
Novel Drug

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors’ cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.

scholarly journals Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

2020 ◽  
Author(s):  
Ghada Alsaleh ◽  
Isabel Panse ◽  
Leo Swadling ◽  
Hanlin Zhang ◽  
Alain Meyer ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Degradation Pathway ◽  
Immune Memory ◽  
Vaccine Responses ◽  
Human T Cells

AbstractOlder adults are at high risk for infectious diseases such as the recent COVID-19 and vaccination seems to be the only long-term solution to the pandemic. While most vaccines are less efficacious in older adults, little is known about the molecular mechanisms that underpin this. Autophagy, a major degradation pathway and one of the few processes known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show induction of autophagy is specifically induced in human vaccine-induced antigen-specific T cells in vivo. Reduced IFNγ secretion by vaccine-induced T cells in older vaccinees correlates with low autophagy. We demonstrate in human cohorts that levels of the endogenous autophagy-inducing metabolite spermidine, fall with age and supplementing it in vitro recovers autophagy and T cell function. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. With these findings we have uncovered novel targets and biomarkers for the development of anti-aging drugs for human T cells, providing evidence for the use of spermidine in improving vaccine immunogenicity in the aged human population.

Propagation of Mouse and Human T Cells with Defined Antigen Specificity and Function

2007 ◽  
pp. 179-197 ◽  
Author(s):  
Peter A. Cohen ◽  
Daniel H. Fowler ◽  
Hyun Kim ◽  
Richard L. White ◽  
Brian J. Czerniecki ◽  
...  
Keyword(s):  
T Cells ◽  
Antigen Specificity ◽  
Human T Cells ◽  
And Function

scholarly journals Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 420-429
Author(s):  
Takayuki Katsuyama ◽  
Hao Li ◽  
Suzanne M Krishfield ◽  
Vasileios C Kyttaris ◽  
Vaishali R Moulton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Elevated Serum ◽  
Splicing Factor ◽  
Type I ◽  
Human T Cells ◽  
Experimental Nephritis ◽  
Ifn Γ

Abstract Objective CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis. Methods T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. Results Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. Conclusion Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.

scholarly journals Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1

2017 ◽  
Vol 215 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Mark Y. Jeng ◽  
Philip A. Hull ◽  
Mingjian Fei ◽  
Hye-Sook Kwon ◽  
Chia-Lin Tsou ◽  
...  
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Memory T Cells ◽  
Cell Metabolism ◽  
Global Gene Expression ◽  
Metabolic Reprogramming ◽  
Transcriptional Reprogramming ◽  
Age Related ◽  
Global Gene Expression Profiling ◽  
And Function

The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

2018 ◽  
Vol 399 (10) ◽  
pp. 1175-1182 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Niklas Beyersdorf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Tricyclic Antidepressant ◽  
Acid Sphingomyelinase ◽  
Human T Cells ◽  
And Function ◽  
Rate Limiting ◽  
Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

scholarly journals Genetic Analysis of Azole Resistance by Transposon Mutagenesis in Saccharomyces cerevisiae

1999 ◽  
Vol 43 (11) ◽  
pp. 2731-2735 ◽  
Author(s):  
D. P. Kontoyiannis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Screening Tool ◽  
Transposon Mutagenesis ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Recessive Mutations ◽  
Novel Drug ◽  
Novel Drug Targets

ABSTRACT The increasing resistance of Candida species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in Saccharomyces cerevisiae, a genetically tractable yeast that is closely related to Candida albicans. This technique, which permits the generation and analysis of multiple random Tn3::LEU2::lacZfusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087–1105, 1994). By using the Tn3::LEU2::lacZlibrary as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g.,PDR5 and CPR1, and in genes previously found to be involved in azole sensitivity, e.g., ERG3. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes,ADA3 and SPT7, are general transcriptional regulators; the third, YMR034c, is a putative sterol transporter. Finally, by screening the Tn3::LEU2::lacZlibrary for lacZ fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of S. cerevisiae to antifungal drugs.

scholarly journals Vasoactive Intestinal Peptide Induces Cell Cycle Arrest and Regulatory Functions in Human T Cells at Multiple Levels

2010 ◽  
Vol 30 (10) ◽  
pp. 2537-2551 ◽  
Author(s):  
Per Anderson ◽  
Elena Gonzalez-Rey
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Cycle Arrest ◽  
Vasoactive Intestinal Peptide ◽  
Molecular Mechanisms ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Experimental Models ◽  
Cycle Arrest ◽  
Human T Cells

ABSTRACT Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory neuropeptide that, by inhibiting Th1-driven responses and inducing the emergence of regulatory T cells (Treg), has been proven successful in the induction of tolerance in various experimental models of autoimmune disorders. Here, we investigate the molecular mechanisms involved in VIP-induced tolerance. VIP treatment in the presence of T-cell receptor (TCR) signaling and CD28 costimulation induced cell cycle arrest in human T cells. VIP blocked G1/S transition and inhibited the synthesis of cyclins D3 and E and the activation of the cyclin-dependent kinases (CDKs) cdk2 and cdk4. This effect was accompanied by maintenance of threshold levels of the CDK inhibitor p27kip1 and impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. Inhibition of interleukin 2 (IL-2) transcription and downregulation of signaling through NFAT, AP-1, and Ras-Raf paralleled the VIP-induced cell cycle arrest. Noteworthy from a functional point of view is the fact that VIP-treated T cells show a regulatory phenotype characterized by high expression of CD25, cytotoxic-T-lymphocyte-associated protein 4 (CTLA4), and Forkhead box protein 3 (FoxP3) and potent suppressive activities against effector T cells. CTLA4 appears to be critically involved in the generation and suppressive activities of VIP-induced Treg. Finally, cyclic AMP (cAMP) and protein kinase A (PKA) activation seems to mediate the VIP-induced cell cycle arrest and Treg generation.

scholarly journals Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

2020 ◽  
Author(s):  
Sherman S. Leung ◽  
Danielle J. Borg ◽  
Domenica A. McCarthy ◽  
Tamar E. Boursalian ◽  
Justen Cracraft ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Soluble Rage ◽  
Human T Cells ◽  
Glycation End Products ◽  
Term Administration ◽  
Pancreatic Lymph Nodes ◽  
And Function

AbstractType 1 diabetes (T1D) is an autoimmune disease with no cure. Therapeutic translation has been hampered by preclinical reproducibility. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (Tregs) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.

Sign in / Sign up

Export Citation Format

Share Document