scholarly journals Metabolic Reprogramming and Intervention During T Cell Exhaustion

2021 ◽  
Author(s):  
Fei Li ◽  
Huiling Liu ◽  
Dan Zhang ◽  
Bingdong Zhu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Metabolism ◽  
T Cell Exhaustion ◽  
Naive T Cells ◽  
Cell Exhaustion ◽  
Naïve T Cells ◽  
T Cell Function ◽  
Prevention And Treatment

Recent studies have shown that T cell metabolism has become a key regulator of T cell function and even can determine T cell function at last. Naïve T cells use fatty acid oxidation (FAO) to meet their energetic demands. Effector T cells mainly rely on aerobic glycolysis to supply energy and synthesize intermediate products. Similar to naïve T cells, memory T cells primarily utilize FAO for energy. Exhausted T cells, which can be induced by continuous activation of T cells upon persistently chronic infections such as tuberculosis, mainly rely on glycolysis for energy. The prevention and treatment of T cell exhaustion is facing great challenges. Interfering T cell metabolism may achieve the goal of prevention and treatment of T cell exhaustion. In this review, we compiled the researches related to exhausted T cell metabolism and put forward the metabolic intervention strategies to reverse T cell exhaustion at different stages to achieve the purpose of preventing and treating T cell exhaustion.

scholarly journals Treatment-Free Intervals Mitigate T-Cell Exhaustion Induced By Continuous CD19xCD3-BiTE® Construct Stimulation in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Nora Zieger ◽  
Alyssa Nicholls ◽  
Jan Wulf ◽  
Gerulf Hänel ◽  
Maryam Kazerani Pasikhani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cell Function ◽  
Granzyme B ◽  
T Cell Exhaustion ◽  
Specific Lysis ◽  
Cell Exhaustion ◽  
T Cell Function

The bispecific T-cell engager (BiTE®) blinatumomab is approved for treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia and applied as continuous infusion over 28 days. The overall response rate to blinatumomab reported in clinical trials was 43 % and correlated to T-cell expansion (Zugmaier et al. 2015). In chronic viral infections, continuous antigen stimulation induces T-cell exhaustion, defined by phenotypic changes and functional impairment (Wherry 2011). Thus, we hypothesized that continuous BiTE® construct stimulation leads to T-cell exhaustion and that a treatment-free interval (TFI) reverses progressive T-cell dysfunction. To simulate continuous application of a BiTE® construct in vitro, T-cell long-term co-cultures were set up. Healthy donor T cells were stimulated in the presence of CD19+ OCI-Ly1 cells for 28 days with AMG 562, a half-life extended CD19 and CD3 specific BiTE® construct. T cells were harvested from the co-culture every 3-4 days between day 7 and 28 and assessed for markers of T-cell exhaustion: (1) AMG 562-mediated cytotoxicity of T cells was evaluated as specific lysis of CD19+ Ba/F3 target cells after 3 days, (2) T-cell expansion during the cytotoxicity assay was calculated as fold change (FC) of CD2+ counts, (3) Cytokine secretion of AMG 562-stimulated T cells was evaluated in co-culture supernatants by cytometric bead array (CBA) or after PMA/Ionomycine stimulation via intracellular cytokine staining (ICCS), (4) T-cell metabolic fitness was determined by Mito- and Glycolytic Stress Test using a Seahorse Analyzer, and (5) expression of the exhaustion-related transcription factor TOX was assessed by multiparameter flow cytometry. In order to assess the effect of a TFI on T-cell function, we cultured T cells and CD19+ OCI-Ly1 cells in the absence of AMG 562 from day 7-14 and 21-28 and compared their activity to T cells stimulated continuously with AMG 562. On day 7 of continuous (CONT) AMG 562 stimulation, we observed high cytotoxic and proliferative potential (% specific lysis=93±0.2, FC=2.9±0.2) as well as high IFN-g and TNF-a secretion analyzed by ICCS (% CD8+IFN-g+TNF-a+=23±6.7). However, cytotoxicity and proliferation decreased gradually until day 28 (% specific lysis=28±8.9; FC=0.6±0.1). CBA analysis confirmed decreasing secretion of IFN-g (day 3: 61113±12482, day 24: 3085±1351 pg/ml) and TNF-a (day 3: 1160±567, day 24: 43±7.6 pg/ml) as well as decreased IL-2 and granzyme B levels in culture supernatants. We furthermore observed highest mitochondrial fitness and basal glycolysis in T cells on day 7 of stimulation (basal OCR=2.2±0.6, maximal OCR=3.7±1.0, SRC=1.5±1.1 pmol/min/1000 cells, basal ECAR=2.0±0.4 mpH/min/1000 cells) which decreased until day 28 (basal OCR=0.4±0.2, maximal OCR=1.5±0.5, SRC=1.0±0.2 pmol/min/1000 cells, basal ECAR=0.5±0.2 mpH/min/1000 cells). In concordance, TOX increased during continuous stimulation (MFI ratio CD8+ day 7=6±0.8 to 12±0.8 on day 28). Strikingly, implementation of a TFI of 7 days led to superior cytotoxicity in T cells compared to continuously stimulated T cells (% specific lysis on day 14 CONT=34±4.2, TFI=99±2.2) and granzyme B production (CD8+; MFI ratio on day 14 CONT=124±11, TFI=303±34). Furthermore, increased proliferation during the cytotoxicity assay was observed in previously rested T cells (FC CONT=0.2±0.0, TFI=1.6±0.6). Although T cell function also decreased over time in TFI T cells, they maintained a strikingly higher cytotoxic potential (CONT=6±4.4, TFI=52±9.9) as well as higher granzyme B production (CONT=25±2, TFI=170±11) on day 28 compared to continuously stimulated T cells. In addition, TFI T cells showed increased IFN-g and TNF-a secretion after PMA/Ionomycine stimulation on day 28 (% CD8+IFN-g+TNF-a+ CONT=21±3.8, TFI=38±11.6). Our in vitro results demonstrate that continuous AMG 562 exposure negatively impacts T-cell function. Comprehensive analysis of T-cell activity in an array of functional assays suggests that continuous BiTE® construct exposure leads to T-cell exhaustion which can be mitigated through TFI. Currently, T cells from patients receiving blinatumomab are being analyzed to confirm the clinical relevance of our findings. Furthermore, RNA-Seq of continuously vs. intermittently AMG 562-exposed T cells will help us to understand underlying transcriptional mechanisms of BiTE® construct induced T-cell exhaustion. Disclosures Zieger: AMGEN Research Munich: Research Funding. Buecklein:Pfizer: Consultancy; Novartis: Research Funding; Celgene: Research Funding; Amgen: Consultancy; Gilead: Consultancy, Research Funding. Brauchle:AMGEN Inc.: Research Funding. Marcinek:AMGEN Research Munich: Research Funding. Kischel:AMGEN: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Subklewe:Gilead Sciences: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Morphosys: Research Funding; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria.

Integrative Genomic Analysis of HIV-Specific CD8+ T Cells Reveals That PD-1 Inhibits T Cell Function by Upregulating the AP-1 Transcription Factor BATF.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 916-916
Author(s):  
Michael Quigley ◽  
Florencia Pereyra ◽  
Bjorn Nilsson ◽  
Quentin Eichbaum ◽  
Boris Julg ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Genomic Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Function

Abstract Abstract 916 T cells responding to chronic infections such as HIV lose the ability to secrete cytokines or to proliferate, functions critical for control of viral replication, in a process termed exhaustion. However the molecular mechanisms of T cell exhaustion are not understood, and few therapeutic targets to reinvigorate exhausted T cells have been identified. We therefore conducted a comprehensive genomic analysis of HIV-specific CD8+ T cells to identify the mechanisms underlying defective function in T cell exhaustion. We used Affymetrix microarrays to study gene expression profiles from sorted Gag-specific tetramer+ CD8+ T cells in two cohorts of HIV-infected individuals that differed in their extent of T cell exhaustion: a) Progressors (n=24), who show chronic elevation of viral load and have defects in HIV-specific T cell cytokine secretion, proliferation and survival; and b) Controllers (n=18), who show spontaneous control of viral replication and have relatively good HIV-specific T cell function. Profiles of Gag-specific CD8+ T cells (median 21,500 cells/sample) from progressors showed marked alterations in gene expression compared with those from controllers (n=518 genes upregulated in progressors, moderated t-statistic >2.0). There was highly significant similarity at the whole-genome level between dysfunctional Gag-specific CD8+ T cells from progressors and exhausted CD8+ T cells in the mouse model of chronic LCMV infection (gene set enrichment analysis, P=4.8e−005), suggesting that T cell exhaustion is associated with an evolutionarily conserved program of gene expression. Next, we determined whether this exhausted signature was influenced by inhibitory signaling via the receptor PD-1, an inhibitory receptor known to be upregulated in expression on exhausted T cells. We developed an in vitro model of PD-1 signaling and identified a unique signature of genes upregulated by PD-1 ligation. The signature of PD-1 induced genes was highly significantly upregulated in profiles from Gag-specific CD8+ T cells in HIV progressors compared to controllers (P=5e−006), and in exhausted CD8+ T cells from the LCMV mouse model (P=2e−004). Thus the signature of T cell exhaustion in humans and mice is driven in part by the consequences of PD-1 signaling. Finally, we asked whether the genes upregulated by PD-1 in exhausted T cells directly inhibit T cell function. PD-1 ligation upregulated the transcription factor BATF in HIV-specific CD8+ T cells and in exhausted CD8+ T cells from the mouse model of LCMV infection. Enforced expression of BATF, an inhibitory member of the AP-1 family, in normal human T cells inhibited proliferation (P=0.02) and IL2 secretion (P=4.5e-05). Infection with LCMV in BATF transgenic mice resulted in marked acceleration of T cell exhaustion compared to wild-type animals, indicating that BATF represses T cell effector functions. Silencing of BATF using shRNA in primary human T cells showed that it was required for PD-1 mediated inhibition of T cell function. In summary, our results demonstrate that 1) PD-1 ligation induces a conserved transcriptional program in exhausted HIV-specific CD8+ T cells and in exhausted LCMV-specific CD8+ T cells in the mouse; 2) this transcriptional program includes the upregulation of genes such as BATF that directly inhibit T cell function. Our data suggest that BATF causes the functional defects seen in T cell exhaustion, and represents a new therapeutic target to rescue T cell function in HIV infection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e115094 ◽  
Author(s):  
Robby Markwart ◽  
Stephanie A. Condotta ◽  
Robert P. Requardt ◽  
Farina Borken ◽  
Katja Schubert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Systemic Inflammation ◽  
Cell Function ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Cell Function

scholarly journals Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Ariana N. Renrick ◽  
Menaka C. Thounaojam ◽  
Maria Teresa P. de Aquino ◽  
Evan Chaudhuri ◽  
Jui Pandhare ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Function ◽  
T Cell Exhaustion ◽  
Functional Link ◽  
Cell Exhaustion ◽  
Cell Functions ◽  
Tumor Bearing ◽  
T Cell Function

Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor–bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8+ T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8+ T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib–induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8+ T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1+ phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155–dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1–mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib–mediated lymphocyte–stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment.

scholarly journals Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Eileen A. Wong ◽  
Louis Joslyn ◽  
Nicole L. Grant ◽  
Edwin Klein ◽  
Philana Ling Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Cell Activity ◽  
Intrinsic Property ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Content Type ◽  
Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

scholarly journals Allogeneic T Cells Utilize Glycolysis As the Predominant Metabolic Pathway to Induce Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2419-2419
Author(s):  
Hung Nguyen ◽  
Kelley MK Haarberg ◽  
Yongxia Wu ◽  
Jianing Fu ◽  
Jessica Lauren Heinrichs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Metabolic Process ◽  
Naive T Cells ◽  
Graft Versus Host ◽  
Naïve T Cells

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematologic malignancies through T cell-mediated graft-versus-leukemia (GVL) effects, but allogeneic T cells often lead to severe graft-versus-host disease (GVHD). Cell metabolism plays pivotal roles in T-cell activation, differentiation, and function. However, understanding of T cell-metabolism is still superficial, and even less is known how metabolism regulates T-cell response to alloantigens and GVHD induction after allo-HCT. In this study, using a high-throughput liquid-and gas-chromatography-based metabolic approach, we compared the metabolic process of allogeneic versus syngeneic T cells at day 4 (early preclinical stage), day 7 (preclinical stage), and day 14 (clinical stage) post bone marrow transplantation (BMT), with naïve T cells as additional controls. Over 180 metabolites were identified and quantified. T cells after being transferred into pre-conditioned recipients were undergoing metabolic reprogramming reflected by attenuated levels of metabolites involving anabolic pathways of lipids, amino acids, nucleotides and carbohydrates in allogeneic and syngeneic T cells compared to those in naïve T cells. In comparison with syngeneic T cells, allogeneic T cells exhibited increased oxidative stress, reflected by higher levels of eicosanoid, cyclooxygenase, and lipoxygenase-oxidized eicosanoids, and decreased levels of antioxidant compounds such as glutathione (GSH) and glutathione disulfide (GSSG). To obtain biomass for robust proliferation followed by alloantigen stimulation, allogeneic T cells further increased pentose phosphate and polyamine synthesis by day 7 post-BMT. We also observed that allogeneic T cells and syngeneic T cells expressed comparable levels of metabolites in fatty acid and glutamine oxidized in tricarboxylic acid (TCA) cycle, which was much lower than those of naïve T cells. Importantly, allogeneic T cells exhibited higher levels of metabolites in glycolysis as compared to syngeneic T cells regardless of time points. Consistently, using Seahorse approach, we also found that allogeneic T cells significantly increased aerobic glycolysis as compared to syngeneic T cells post-BMT, whereas oxidative phosphorylation was similar. Moreover, blocking glycolysis with 2-deoxyglucose remarkably inhibited donor T-cell proliferation, expansion and Th1 differentiation after allo-BMT. Thus, aerobic glycolysis rather than mitochondrial oxidative phosphorylation is the preferential metabolic process required for the optimal expansion and activation of allogeneic T cells. Given mechanistic target of rapamycin (mTOR) plays an essential role in controlling T-cell metabolism particularly in glycolysis, we hypothesized that targeting mTOR would prevent GVHD by inhibiting glycolytic metabolism. Using pharmacological and genetic approaches, we unequivocally demonstrated that mTOR, especially mTORC1, was essential for T-cell glycolytic activity and for GVHD induction. Mechanistically, mTORC1 promoted T-cell activation, expansion, Th1 differentiation, and migration into GVHD target organs, but inhibited the generation of induced T regulatory cells. In conclusion, the current work provides compelling evidence that allogeneic T cells utilize glycolysis as a predominant metabolic process after BMT. Furthermore, we validate glycolysis or its key regulator, such as mTORC1, to be a valid therapeutic target for the control of GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

2021 ◽  
Author(s):  
Yini Sun ◽  
Renyu Ding ◽  
Yukun Chang ◽  
Jiuming Li ◽  
Xiaochun Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

scholarly journals Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3139-3146 ◽  
Author(s):  
Matilde León-Ponte, ◽  
Gerard P. Ahern ◽  
Peta J. O'Connell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Function ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Alternative Mechanism ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
And Function

Abstract Although typically considered a neurotransmitter, there is substantial evidence that serotonin (5-HT) plays an important role in the pathogenesis of inflammatory disorders. Despite these findings, the precise role of 5-HT in modulating immune function, particularly T-cell function, remains elusive. We report that naive T cells predominantly express the type 7 5-HT receptor (5-HTR), and expression of this protein is substantially enhanced on T-cell activation. In addition, T-cell activation leads to expression of the 5-HT1B and 5-HT2A receptors. Significantly, exogenous 5-HT induces rapid phosphorylation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and IκBα in naive T cells. 5-HT–induced activation of ERK1/2 and NFκB is inhibited by preincubation with a specific 5-HT7 receptor antagonist. Thus, 5-HT signaling via the 5-HT7 receptor may contribute to early T-cell activation. In turn, 5-HT synthesized by T cells may act as an autocrine factor. Consistent with this hypothesis, we found that inhibition of 5-HT synthesis with parachlorophenylalanine (PCPA) impairs T-cell activation and proliferation. Combined, these data demonstrate a fundamental role for 5-HT as an intrinsic cofactor in T-cell activation and function and suggest an alternative mechanism through which immune function may be regulated by indoleamine 2,3-dioxygenase–mediated catabolism of tryptophan.

mTORC1 regulates CD8+ T-cell glucose metabolism and function independently of PI3K and PKB

2013 ◽  
Vol 41 (2) ◽  
pp. 681-686 ◽  
Author(s):  
David K. Finlay
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glucose Metabolism ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cell Metabolism ◽  
Present Review ◽  
Glycolytic Metabolism ◽  
Cell Systems ◽  
T Cell Function

Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells rely more on oxidative glucose metabolism, there is growing interest in understanding how T-cell metabolism relates to T-cell function. The mTORC1 (mammalian target of rapamycin complex 1) has a crucial role to determine the balance between effector and regulatory T-cell differentiation, but is also described as a key regulator of metabolism in non-immune cell systems. The present review explores the relationship between these diverse functions of mTORC1 with regard to T-cell function. In many cell systems, mTORC1 couples PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B), also known as Akt, with the control of glucose uptake and glycolysis. However, this is not the case in activated CD8+ CTLs (cytotoxic T-lymphocytes) where PI3K/PKB signalling is dispensable for the elevated levels of glycolysis that is characteristic of activated T-cells. Nevertheless, mTORC1 is still essential for glycolytic metabolism in CD8+ T-cells, and this reflects the fact that mTORC1 does not lie downstream of PI3K/PKB signalling in CD8+ T-cells, as is the case in many other cell systems. mTORC1 regulates glucose metabolism in CTLs through regulating the expression of the transcription factor HIF1α (hypoxia-inducible factor 1α). Strikingly, HIF1α functions to couple mTORC1 with a diverse transcriptional programme that extends beyond the control of glucose metabolism to the regulation of multiple key T-cell functions. The present review discusses the idea that mTORC1/HIF1α signalling integrates the control of T-cell metabolism and T-cell function.

scholarly journals IgG Immune Complexes Inhibit Naïve T Cell Proliferation and Suppress Effector Function in Cytotoxic T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Wissam Charab ◽  
Matthew G. Rosenberger ◽  
Haridha Shivram ◽  
Justin M. Mirazee ◽  
Moses Donkor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Complexes ◽  
Cell Function ◽  
Memory T Cells ◽  
Cytotoxic T Cells ◽  
Cell Subset ◽  
Phenotypic Analysis ◽  
Naive T Cells ◽  
Naïve T Cells

Elevated levels of circulating immune complexes are associated with autoimmunity and with worse prognoses in cancer. Here, we examined the effects of well-defined, soluble immune complexes (ICs) on human peripheral T cells. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of a subset of naïve T cells but stimulate the division of another naïve-like T cell subset. Phenotypic analysis by multi-parameter flow cytometry and RNA-Seq were used to characterize the inhibited and stimulated T cells revealing that the inhibited subset presented immature features resembling those of recent thymic emigrants and non-activated naïve T cells, whereas the stimulated subset exhibited transcriptional features indicative of a more differentiated, early memory progenitor with a naïve-like phenotype. Furthermore, we show that while IgG1-ICs do not profoundly inhibit the proliferation of memory T cells, IgG1-ICs suppress the production of granzyme-β and perforin in cytotoxic memory T cells. Our findings reveal how ICs can link humoral immunity and T cell function.

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