GOT1 regulates CD8+ effector and memory T cell generation

Xu, Wei; Patel, Chirag H.; Zhao, Liang; Sun, Im-Hong; Oh, Min Hee; Sun, Im-Meng; Helms, Rachel; Wen, Jiayu; Powell, Jonathan D.

doi:10.1016/j.celrep.2022.111987

Cited by 14 publications

(11 citation statements)

References 33 publications

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“…4C). Consistent with recent results shown for Got1 −/− T cells (37), silencing Got1 promoted a slight reduction in CD8 T cell proliferation (Fig. 4E); however, the proliferation of Got1-knockdown-but not control-CD8 T cells was selectively reduced when aspartate was removed from the cell culture medium, while viability was unchanged (Fig.…”

Section: Got1 Supports Cd8 Teff Cell Proliferation In Vivosupporting

confidence: 92%

“…4, G and H ). Recently published work by Xu et al ( 37 ) established similar requirements for Got1 in mediating T cell–mediated antitumor responses. Genetic ablation of Got1 using T cell–specific conditional deletion in mice ( Got1 fl/fl CD4Cre ) resulted in poor control of experimental tumors (i.e., B16 melanoma) due in part to reduced perforin expression and cytotoxic T lymphocyte–killing capacity by Got1-deficient Teff cells ( 37 ).…”

Section: Discussionmentioning

confidence: 87%

“…Recently published work by Xu et al ( 37 ) established similar requirements for Got1 in mediating T cell–mediated antitumor responses. Genetic ablation of Got1 using T cell–specific conditional deletion in mice ( Got1 fl/fl CD4Cre ) resulted in poor control of experimental tumors (i.e., B16 melanoma) due in part to reduced perforin expression and cytotoxic T lymphocyte–killing capacity by Got1-deficient Teff cells ( 37 ). It is unclear whether Got2, which is localized in the mitochondria, can functionally compensate for Got1 to maintain intracellular aspartate at sufficient levels to support T cell function.…”

Section: Discussionmentioning

confidence: 87%

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¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

Ma,

Dahabieh,

DeCamp

et al. 2024

Sci. Adv.

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Infusion of 13 C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13 C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes –infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)—which regulates de novo aspartate synthesis—for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

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Section: Got1 Supports Cd8 Teff Cell Proliferation In Vivosupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

Ma,

Dahabieh,

DeCamp

et al. 2024

Sci. Adv.

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“…DPEP1, conversely, is associated with neutrophil-mediated inflammatory responses, facilitating neutrophil recruitment from to bloodstream to inflamed tissue by acting as a physical adhesion receptor ( 72 ). GOT1 plays a role in T cell exhaustion, as it maintains chronic immune responses by regulating CD8+ effector and memory T cell generation ( 73 , 74 ). In contrast, upregulation of IGFALS shows activation of the innate immune response.…”

Section: Discussionmentioning

confidence: 99%

Serum proteomics reveals a tolerant immune phenotype across multiple pathogen taxa in wild vampire bats

Vicente-Santos,

Lock,

Allira

et al. 2023

Front. Immunol.

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Bats carry many zoonotic pathogens without showing pronounced pathology, with a few exceptions. The underlying immune tolerance mechanisms in bats remain poorly understood, although information-rich omics tools hold promise for identifying a wide range of immune markers and their relationship with infection. To evaluate the generality of immune responses to infection, we assessed the differences and similarities in serum proteomes of wild vampire bats (Desmodus rotundus) across infection status with five taxonomically distinct pathogens: bacteria (Bartonella spp., hemoplasmas), protozoa (Trypanosoma cruzi), and DNA (herpesviruses) and RNA (alphacoronaviruses) viruses. From 19 bats sampled in 2019 in Belize, we evaluated the up- and downregulated immune responses of infected versus uninfected individuals for each pathogen. Using a high-quality genome annotation for vampire bats, we identified 586 serum proteins but found no evidence for differential abundance nor differences in composition between infected and uninfected bats. However, using receiver operating characteristic curves, we identified four to 48 candidate biomarkers of infection depending on the pathogen, including seven overlapping biomarkers (DSG2, PCBP1, MGAM, APOA4, DPEP1, GOT1, and IGFALS). Enrichment analysis of these proteins revealed that our viral pathogens, but not the bacteria or protozoa studied, were associated with upregulation of extracellular and cytoplasmatic secretory vesicles (indicative of viral replication) and downregulation of complement activation and coagulation cascades. Additionally, herpesvirus infection elicited a downregulation of leukocyte-mediated immunity and defense response but an upregulation of an inflammatory and humoral immune response. In contrast to our two viral infections, we found downregulation of lipid and cholesterol homeostasis and metabolism with Bartonella spp. infection, of platelet-dense and secretory granules with hemoplasma infection, and of blood coagulation pathways with T. cruzi infection. Despite the small sample size, our results suggest that vampire bats have a similar suite of immune mechanisms for viruses distinct from responses to the other pathogen taxa, and we identify potential biomarkers that can expand our understanding of pathogenesis of these infections in bats. By applying a proteomic approach to a multi-pathogen system in wild animals, our study provides a distinct framework that could be expanded across bat species to increase our understanding of how bats tolerate pathogens.

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“…GOT1 catalyzes the reaction that converts aspartate and α-ketoglutarate to oxaloacetate and glutamate [ 85 , 86 ]. In mice, GOT1 expression was higher in proliferating CD8 + effector T cells than in quiescent CD8 + memory T cells [ 87 ]. The lower abundance of GOT1 in CD4 + cells of GHR -KO pigs may therefore point to a reduced activation state and a shift towards metabolic quiescence.…”

Section: Discussionmentioning

confidence: 99%

Effects of GHR Deficiency and Juvenile Hypoglycemia on Immune Cells of a Porcine Model for Laron Syndrome

Schilloks¹,

Giese²,

Hinrichs

et al. 2023

Biomolecules

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Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4− and CD4+ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4+CD8α− subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4+ and CD4− lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.

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GOT1 regulates CD8+ effector and memory T cell generation

Cited by 14 publications

References 33 publications

¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

Serum proteomics reveals a tolerant immune phenotype across multiple pathogen taxa in wild vampire bats

Effects of GHR Deficiency and Juvenile Hypoglycemia on Immune Cells of a Porcine Model for Laron Syndrome

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GOT1 regulates CD8+ effector and memory T cell generation

Cited by 14 publications

References 33 publications

13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

Serum proteomics reveals a tolerant immune phenotype across multiple pathogen taxa in wild vampire bats

Effects of GHR Deficiency and Juvenile Hypoglycemia on Immune Cells of a Porcine Model for Laron Syndrome

Contact Info

Product

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¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells

¹³ C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells