scholarly journals Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans

2022 ◽  
pp. ji2100194
Author(s):  
Francesco Nicoli ◽  
Mariela P. Cabral-Piccin ◽  
Laura Papagno ◽  
Eleonora Gallerani ◽  
Mathieu Fusaro ◽  
...  
Keyword(s):  
T Cells ◽  
Lipid Metabolism ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
Elderly Humans

Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Immunity ◽  
2021 ◽  
Author(s):  
David R. Collins ◽  
Jonathan M. Urbach ◽  
Zachary J. Racenet ◽  
Umar Arshad ◽  
Karen A. Power ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Functional Impairment

scholarly journals Mitochondrial Dysfunction Associates With Acute T Lymphocytopenia and Impaired Functionality in COVID-19 Patients

2022 ◽  
Vol 12 ◽  
Author(s):  
Yufei Mo ◽  
Kelvin Kai-Wang To ◽  
Runhong Zhou ◽  
Li Liu ◽  
Tianyu Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mitochondrial Dysfunction ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
Cell Loss ◽  
Cd8 T Cell ◽  
Underlying Mechanism ◽  
T Cell Subsets ◽  
Effector Memory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

scholarly journals Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Teresa Manzo ◽  
Boone M. Prentice ◽  
Kristin G. Anderson ◽  
Ayush Raman ◽  
Aislyn Schalck ◽  
...  
Keyword(s):  
Fatty Acids ◽  
T Cells ◽  
Lipid Metabolism ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Metabolic Reprogramming ◽  
Long Chain Fatty Acids ◽  
Cell Functions ◽  
Long Chain ◽  
Chain Fatty Acids

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

scholarly journals Functional Impairment of Cytomegalovirus Specific CD8 T Cells Predicts High-Level Replication After Renal Transplantation

2008 ◽  
Vol 8 (5) ◽  
pp. 990-999 ◽  
Author(s):  
F. M. Mattes ◽  
A. Vargas ◽  
J. Kopycinski ◽  
E. G. Hainsworth ◽  
P. Sweny ◽  
...  
Keyword(s):  
T Cells ◽  
Renal Transplantation ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
High Level

scholarly journals AB0028 EXPRESSION OF FATTY ACID TRANSPORTERS AND FREE FATTY ACID UPTAKE IN CD8+ T CELLS IN AUTOIMMUNE ARTHRITIS PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1047.2-1048
Author(s):  
S. Keck ◽  
F. V. Kraus ◽  
H. M. Lorenz ◽  
M. Souto-Carneiro
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acid ◽  
Disease Activity ◽  
Cd8 T Cells ◽  
Disease Duration ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Effector Functions

Background:RA CD8+ T cells (CD8s) have been shown to vastly contribute to tissue damage and RA disease activity by presenting and maintaining an active effector phenotype promoting autoinflammation. In order to meet their high metabolic requirements RA CD8s alter not only their glycolytic and glutaminolytic profiles, but also rely on increased lipid metabolism characterized by increased free fatty acid (FFA) uptake and lipid biosynthesis.Objectives:In order to classify the importance of lipid metabolism in RA CD8s in terms of initiation and perpetuation of effector functions and therefore exploring potential novel therapy targeting points or biomarkers additional investigations have to been made. By analysing FFA uptake and the expression of free fatty acid transporters (FAT) upon TCR-stimulation in RA, PsA, SpA patients and healthy controls (HC), we aimed to further characterize the importance of RA CD8s´ lipid metabolism.Methods:Blood samples from 23 RA patients, 22 SpA patients, 20 PsA patients and 7 HC recruited at Heidelberg University Hospital were processed via negative magnetic separation selection to obtain purified CD8s. CD8s were cultured for 72 hours in [1,6-13C] glucose containing medium in the presence of anti-CD3 and anti-CD28. FFA uptake was measured by Palmitate-Bodipy 488 staining (ThermoFisher), the expression of FAT CD36, FABP4 and GPR84 besides CD69, CD36, CD45RA, CD3 and CD8 were assessed by FACS analysis.Ethic approval NR: S-096/2016.Results:The intake of the FFA palmitate by CD8s was higher in all patients groups than in HC (p < 0,05). In all three diseases´ stimulated CD8s, unlike in the HC group, the expression of GPR84 was inversely correlating to the expression of CD69 (Spearman r < -0,62). In patient´s stimulated CD8s the expression of GPR84 tended to be lower in RA and PSA effector memory (EM) CD8s. In RA and HC the expression of FABP4 tended to be lower in the naive CD8+ subset when compared to the effector subset. HC naive and effector CD8+ subsets had a higher expression of CD36 than in the patient groups. In RA and SPA patients the expression of FAT correlated with clinical variables. In RA DAS28 and CRP inversely correlated with CD36 (MFI), and disease duration with FABP4 as well. In SPA CRP and BASDAI inversely correlated with FABP4 while disease duration had a negative correlation with CD36 (MFI). GPR84 (MFI) had an inverted relationship to BASDAI. While the BMI was directly correlated with the expression of CD36 in RA, this relationship was inverted in SPA.Conclusion:A high free fatty acid uptake seems to characterize autoimmune arthritis CD8+ T cells. The gain of effector functions appears to be connected to changes in the expression of different fatty acid transporters on the surface of CD8+ T cells. The correlation between the expression of fatty acid transporters and clinical parameters (specially disease activity scores) in RA and SPA suggests that they could potentially be used as biomarkers for disease activity and progression.Acknowledgements:We thank all the individuals involved in the study for their participation.Disclosure of Interests:None declared

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