Targeting age‐specific changes in CD4
            +
            T cell metabolism ameliorates alloimmune responses and prolongs graft survival

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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Cell-cell interaction in graft rejection responses: induction of anti-allo-class I H-2 tolerance is prevented by immune responses against allo-class II H-2 antigens coexpressed on tolerogen.

Journal of Experimental Medicine ◽

10.1084/jem.175.1.99 ◽

1992 ◽

Vol 175 (1) ◽

pp. 99-109 ◽

Cited By ~ 6

Author(s):

S Hori ◽

S Kitagawa ◽

H Iwata ◽

T Ochiai ◽

K Isono ◽

...

Keyword(s):

T Cell ◽

Graft Survival ◽

Cytotoxic T Lymphocyte ◽

Interleukin 2 ◽

Cell Interaction ◽

Class Ii ◽

Cd4 T Cell ◽

Class I ◽

Prolonged Survival ◽

Spleen Cells

The intravenous sensitization of C57BL/6 (B6) mice with class I H-2-disparate B6-C-H-2bm1 (bm1) spleen cells results in almost complete abrogation of anti-bm1 CD8+ helper (proliferative and interleukin 2-producing) T cell (Th) activities. Although an appreciable portion of CD8+ cytotoxic T lymphocyte (CTL) precursors themselves remained after this regimen, such a residual CTL activity was eliminated after the engrafting of bm1 grafts, and these grafts exhibited prolonged survival. In contrast, the intravenous sensitization with (bm1 x B6-C-H-2bm12 [bm12])F1 cells instead of bm1 cells failed to induce the prolongation of bm1 graft survival as well as bm12 and (bm1 x bm12)F1 graft survival. In the (bm1 x bm12)F1-presensitized B6 mice before as well as after the engrafting of bm1 grafts, anti-bm1 CTL responses that were comparable to or slightly stronger than those observed in unpresensitized mice were induced in the absence of anti-bm1 Th activities. bm1 graft survival was also prolonged by intravenous presensitization with a mixture of bm1 and bm12 cells but not with a mixture of bm1 and (bm1 x bm12)F1 cells. The capacity of CD4+ T cells to reject bm12 grafts was eliminated by intravenous presensitization with antigen-presenting cell (APC)-depleted bm12 spleen cells. However, intravenous presensitization with APC-depleted (bm1 x bm12)F1 cells failed to induce the prolongation of bm1 graft survival under conditions in which appreciably prolonged bm12 graft survival was induced. More surprisingly, bm1 graft survival was not prolonged even when the (bm1 x bm12)F1 cell presensitization was performed in CD4+ T cell-depleted B6 mice. This contrasted with the fact that conventional class I-disparate grafts capable of activating self Ia-restricted CD4+ as well as allo-class I-reactive CD8+ Th exhibited prolonged survival in CD4+ T cell-depleted, class I-disparate cell-presensitized mice. These results indicate that: (a) intravenous presensitization with class I- and II-disparate cells fails to reduce anti-allo-class I rejection responses that would otherwise be eliminated using only class I-disparate cells; (b) such failure is generated according to the coexpression of both classes of alloantigens on a single cell as tolerogen; and (c) allo-class II antigens coexpressed on tolerogen function to activate CD4+ as well as non-CD4+ Th leading to the generation of anti-class I effector T cell responses.

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T Cell Metabolism and Memory

Blood ◽

10.1182/blood-2018-99-109535 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. SCI-6-SCI-6

Author(s):

Jeffrey C Rathmell

Keyword(s):

T Cells ◽

T Cell ◽

Glucose Transporter ◽

Cell Metabolism ◽

Effector Function ◽

Glutamine Metabolism ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Th1 Cells ◽

Inflammatory Models

Abstract Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that CD4 T cell subsets are metabolically distinct. These specific metabolic programs may allow new understanding and approaches to manipulate immunity. Using metabolic network analysis of metabolomics and proteomics we defined several metabolic nodes differentially utilized by CD4 T cell subsets, including glutamine metabolism. By genetically deleting the glucose transporter Glut1 or the glutaminolysis enzyme, Glutaminase (GLS), we have shown that glycolysis and glutaminolysis are both used by activated T cells. All effector T cells require glycolysis, but we found that Th17 cells preferentially require GLS while Th1 cells are actively impaired by this enzyme. Thus, inhibition of GLS both reduces Th17 responses and promotes differentiation of Th1 cells and can lead to signs of T cell exhaustion. We show that GLS-deficiency can protect against Th17-mediated inflammatory models and also can augment effector function of Th1 CAR-T cells against B cell targets. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector populations to both suppress inflammation or promote effector function. Disclosures Rathmell: Calithera: Research Funding.

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CD4 T Cell Metabolism Is a Major Contributor of HIV Infectivity and Reservoir Persistence

Immunometabolism ◽

10.20900/immunometab20200005 ◽

2020 ◽

Keyword(s):

T Cell ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Major Contributor

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Faculty Opinions recommendation of Normalization of CD4+ T cell metabolism reverses lupus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725352924.793518532 ◽

2016 ◽

Author(s):

Barry Rouse

Keyword(s):

T Cell ◽

Cell Metabolism ◽

Cd4 T Cell

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Genome-wide metabolic model to improve understanding of CD4+ T cell metabolism, immunometabolism and application in drug design

Molecular BioSystems ◽

10.1039/c5mb00480b ◽

2016 ◽

Vol 12 (2) ◽

pp. 431-443 ◽

Cited By ~ 9

Author(s):

Feifei Han ◽

Gonghua Li ◽

Shaoxing Dai ◽

Jingfei Huang

Keyword(s):

T Cells ◽

T Cell ◽

Drug Design ◽

Drug Development ◽

Cell Metabolism ◽

Metabolic Model ◽

Cd4 T Cell ◽

Model Based ◽

Genome Wide

Model-based investigation of the metabolism and immunometabolism of CD4+ T cells (CD4T1670) and the application of CD4T1670 in drug development.

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TARGETING CD4+ T CELL METABOLISM PROVIDES AN EFFECTIVE AND AGE-SPECIFIC IMMUNOSUPPRESSION

Transplantation Journal ◽

10.1097/01.tp.0000698708.39999.42 ◽

2020 ◽

Vol 104 (S3) ◽

pp. S89-S89

Author(s):

Yeqi Nian ◽

Timm Heinbokel ◽

Koichiro Minami ◽

Ryoichi Maenosono ◽

Jasper Iske ◽

...

Keyword(s):

T Cell ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Specific Immunosuppression

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Atherosclerosis Impairs Naive CD4 T-Cell Responses via Disruption of Glycolysis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314189 ◽

2021 ◽

Author(s):

Dalia E. Gaddis ◽

Lindsey E. Padgett ◽

Runpei Wu ◽

Anh Nguyen ◽

Chantel McSkimming ◽

...

Keyword(s):

Cardiovascular Disease ◽

T Cells ◽

T Cell ◽

Apolipoprotein E ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Standard Laboratory ◽

Apolipoprotein E Knockout Mice ◽

Standard Laboratory Diet

Objective: CD4 T cells are important regulators of atherosclerotic progression. The metabolic profile of CD4 T cells controls their signaling and function, but how atherosclerosis affects T-cell metabolism is unknown. Here, we sought to determine the impact of atherosclerosis on CD4 T-cell metabolism and the contribution of such alterations to atheroprogression. Approach and Results: Using PCR arrays, we profiled the expression of metabolism genes in CD4 T cells from atherosclerotic, apolipoprotein-E knockout mice fed a Western diet. These cells exhibited dysregulated expression of genes critically involved in glycolysis and fatty acid degradation, compared with those from animals fed a standard laboratory diet. We examined how T-cell metabolism was changed in standard laboratory diet or Western diet–fed apolipoprotein-E knockout mice or humans by measuring glucose uptake, activation, and proliferation in CD4 T cells. We found that naive CD4 T cells from Western diet–fed apolipoprotein-E knockout mice failed to uptake glucose and thus displayed impaired proliferation and activation, compared with CD4 T cells from standard laboratory diet–fed animals. Similarly, as in mice, we observed that naive CD4 T-cell frequencies were reduced in circulation of human subjects with high cardiovascular disease compared with low cardiovascular disease, as assessed clinically based on medically necessary coronary angiography. Naive T cells from high cardiovascular disease subjects also showed reduced proliferative capacity. Conclusions: These results highlight the dysfunctional changes that occur in CD4 T-cell metabolism and immune responses during atherosclerosis. Targeting metabolic pathways within naive CD4 T cells could thus yield novel therapeutic approaches for improving CD4 T-cell responses against atheroprogression.

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