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Article ; Online: STAT6 tunes maximum T cell IL-4 production from stochastically regulated Il4 alleles.

Kyle, Ryan L / Prout, Melanie / Le Gros, Graham / Robinson, Marcus J

2024 Volume 102, Issue 3, Page(s) 194–211

Abstract: T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus ...

Abstract	T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL-4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co-expressors, dual allele transcription occurs for only short periods, limiting per-cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL-4 output was derived predominantly from single alleles, but co-expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL-4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL-4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression.
MeSH term(s)	Animals ; Mice ; Alleles ; Cytokines ; Interleukin-4 ; RNA, Messenger/genetics ; Th2 Cells
Chemical Substances	Cytokines ; Interleukin-4 (207137-56-2) ; RNA, Messenger ; Stat6 protein, mouse ; Il4 protein, mouse
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12726
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Article ; Online: Unraveling the Complex Interplay Between T Cell Metabolism and Function.

Geltink, Ramon I Klein / Kyle, Ryan L / Pearce, Erika L

Annual review of immunology

2018 Volume 36, Page(s) 461–488

Abstract: Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, ... ...

Abstract	Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.
MeSH term(s)	Animals ; Biomarkers ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Energy Metabolism ; Humans ; Immunity ; Immunologic Memory ; Immunotherapy ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Mitochondria/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Biomarkers ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2018-04-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-042617-053019
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Article: IL-4 Is a Key Requirement for IL-4- and IL-4/IL-13-Expressing CD4 Th2 Subsets in Lung and Skin.

Prout, Melanie Sarah / Kyle, Ryan L / Ronchese, Franca / Le Gros, Graham

Frontiers in immunology

2018 Volume 9, Page(s) 1211

Abstract: Although IL-4 is long associated with CD4 Th2 immune responses, its role in Th2 subset development in non-lymphoid tissues is less clear. We sought to better define IL-4's role in CD4 Th2 responses by using transgenic mice that express a dual IL-4 AmCyan/ ...

Abstract	Although IL-4 is long associated with CD4 Th2 immune responses, its role in Th2 subset development in non-lymphoid tissues is less clear. We sought to better define IL-4's role in CD4 Th2 responses by using transgenic mice that express a dual IL-4 AmCyan/IL-13 DsRed (IL-4AC/IL-13DR) fluorescent reporter on an IL-4-sufficient or IL-4-deficient background. Using primary Th2 immune response models against house dust mite or
MeSH term(s)	Allergens/immunology ; Animals ; Biomarkers ; Gene Expression ; Genotype ; Immunization ; Immunophenotyping ; Interleukin-13/genetics ; Interleukin-13/metabolism ; Interleukin-4/genetics ; Interleukin-4/metabolism ; Lung/immunology ; Lung/metabolism ; Lymph Nodes/immunology ; Lymph Nodes/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Biological ; Pyroglyphidae/immunology ; Skin/immunology ; Skin/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Th2 Cells/immunology ; Th2 Cells/metabolism
Chemical Substances	Allergens ; Biomarkers ; Interleukin-13 ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2018-06-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01211
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Article ; Online: Inflammatory macrophage dependence on NAD

Cameron, Alanna M / Castoldi, Angela / Sanin, David E / Flachsmann, Lea J / Field, Cameron S / Puleston, Daniel J / Kyle, Ryan L / Patterson, Annette E / Hässler, Fabian / Buescher, Joerg M / Kelly, Beth / Pearce, Erika L / Pearce, Edward J

Nature immunology

2019 Volume 20, Issue 4, Page(s) 420–432

Abstract: The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme ... ...

Abstract	The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD
MeSH term(s)	Acrylamides/pharmacology ; Animals ; Cells, Cultured ; Cytokines/metabolism ; DNA Damage ; Electron Transport Complex III/metabolism ; HEK293 Cells ; Humans ; Inflammation/metabolism ; Macrophage Activation ; Macrophages/drug effects ; Macrophages/enzymology ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; NAD/metabolism ; Nicotinamide Phosphoribosyltransferase/metabolism ; Piperidines/pharmacology ; Reactive Oxygen Species/metabolism
Chemical Substances	Acrylamides ; Cytokines ; N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide ; Piperidines ; Reactive Oxygen Species ; NAD (0U46U6E8UK) ; Nicotinamide Phosphoribosyltransferase (EC 2.4.2.12) ; nicotinamide phosphoribosyltransferase, mouse (EC 2.4.2.12) ; Electron Transport Complex III (EC 7.1.1.8)
Language	English
Publishing date	2019-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-019-0336-y
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Article ; Online: Thymic stromal lymphopoietin drives the development of IL-13

Ochiai, Sotaro / Jagot, Ferdinand / Kyle, Ryan L / Hyde, Evelyn / White, Ruby F / Prout, Melanie / Schmidt, Alfonso J / Yamane, Hidehiro / Lamiable, Olivier / Le Gros, Graham / Ronchese, Franca

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 5, Page(s) 1033–1038

Abstract: T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL- ... ...

Abstract	T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL-4
MeSH term(s)	Adoptive Transfer ; Animals ; Cell Differentiation/immunology ; Cytokines/deficiency ; Cytokines/genetics ; Cytokines/immunology ; Female ; Humans ; Interleukin-13/genetics ; Interleukin-13/metabolism ; Interleukin-4/genetics ; Interleukin-4/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Receptors, Interleukin-7/metabolism ; Th2 Cells/classification ; Th2 Cells/cytology ; Th2 Cells/immunology
Chemical Substances	Cytokines ; Interleukin-13 ; Receptors, Interleukin-7 ; thymic stromal lymphopoietin ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2018--30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1714348115
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Article ; Online: Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function.

Field, Cameron S / Baixauli, Francesc / Kyle, Ryan L / Puleston, Daniel J / Cameron, Alanna M / Sanin, David E / Hippen, Keli L / Loschi, Michael / Thangavelu, Govindarajan / Corrado, Mauro / Edwards-Hicks, Joy / Grzes, Katarzyna M / Pearce, Edward J / Blazar, Bruce R / Pearce, Erika L

Cell metabolism

2019 Volume 31, Issue 2, Page(s) 422–437.e5

Abstract: Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake ... ...

Abstract	Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
MeSH term(s)	Animals ; Cell Line, Tumor ; DNA, Mitochondrial/metabolism ; Fatty Acid-Binding Proteins/physiology ; Humans ; Interferon Type I/metabolism ; Interleukin-10/metabolism ; Lipid Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/pathology
Chemical Substances	DNA, Mitochondrial ; FABP5 protein, human ; Fatty Acid-Binding Proteins ; IL10 protein, human ; Interferon Type I ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2019-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2019.11.021
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Article ; Online: Phosphoinositide acyl chain saturation drives CD8

Edwards-Hicks, Joy / Apostolova, Petya / Buescher, Joerg M / Maib, Hannes / Stanczak, Michal A / Corrado, Mauro / Klein Geltink, Ramon I / Maccari, Maria Elena / Villa, Matteo / Carrizo, Gustavo E / Sanin, David E / Baixauli, Francesc / Kelly, Beth / Curtis, Jonathan D / Haessler, Fabian / Patterson, Annette / Field, Cameron S / Caputa, George / Kyle, Ryan L /

Soballa, Melanie / Cha, Minsun / Paul, Harry / Martin, Jacob / Grzes, Katarzyna M / Flachsmann, Lea / Mitterer, Michael / Zhao, Liang / Winkler, Frances / Rafei-Shamsabadi, David Ali / Meiss, Frank / Bengsch, Bertram / Zeiser, Robert / Puleston, Daniel J / O'Sullivan, David / Pearce, Edward J / Pearce, Erika L

Nature immunology

2023 Volume 24, Issue 3, Page(s) 516–530

Abstract: How lipidome changes support ... ...

Abstract	How lipidome changes support CD8
MeSH term(s)	Phosphatidylinositols/metabolism ; Phosphatidylinositol Phosphates ; Signal Transduction ; Type C Phospholipases/metabolism ; CD8-Positive T-Lymphocytes/metabolism
Chemical Substances	Phosphatidylinositols ; Phosphatidylinositol Phosphates ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2023-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01419-y
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Article ; Online: Fever supports CD8

O'Sullivan, David / Stanczak, Michal A / Villa, Matteo / Uhl, Franziska M / Corrado, Mauro / Klein Geltink, Ramon I / Sanin, David E / Apostolova, Petya / Rana, Nisha / Edwards-Hicks, Joy / Grzes, Katarzyna M / Kabat, Agnieszka M / Kyle, Ryan L / Fabri, Mario / Curtis, Jonathan D / Buck, Michael D / Patterson, Annette E / Regina, Annamaria / Field, Cameron S /

Baixauli, Francesc / Puleston, Daniel J / Pearce, Edward J / Zeiser, Robert / Pearce, Erika L

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 25

Abstract: Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated ... ...

Abstract	Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8
MeSH term(s)	Animals ; Antineoplastic Agents/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/ultrastructure ; Cytokines/biosynthesis ; Fever/immunology ; Glucose/metabolism ; Leukemia, Myeloid/immunology ; Leukemia, Myeloid/pathology ; Leukemia, Myeloid/prevention & control ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Models, Biological ; Protein Biosynthesis ; Temperature ; Mice
Chemical Substances	Antineoplastic Agents ; Cytokines ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2023752118
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Article ; Online: Acetate Promotes T Cell Effector Function during Glucose Restriction.

Qiu, Jing / Villa, Matteo / Sanin, David E / Buck, Michael D / O'Sullivan, David / Ching, Reagan / Matsushita, Mai / Grzes, Katarzyna M / Winkler, Frances / Chang, Chih-Hao / Curtis, Jonathan D / Kyle, Ryan L / Van Teijlingen Bakker, Nikki / Corrado, Mauro / Haessler, Fabian / Alfei, Francesca / Edwards-Hicks, Joy / Maggi, Leonard B / Zehn, Dietmar /

Egawa, Takeshi / Bengsch, Bertram / Klein Geltink, Ramon I / Jenuwein, Thomas / Pearce, Edward J / Pearce, Erika L

Cell reports

2019 Volume 27, Issue 7, Page(s) 2063–2074.e5

Abstract: Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For ... ...

Abstract	Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8
MeSH term(s)	Acetate-CoA Ligase/immunology ; Acetates/immunology ; Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cell Line, Tumor ; Glucose/immunology ; Humans ; Interferon-gamma/immunology ; Mice ; Neoplasm Proteins/immunology ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/pathology
Chemical Substances	Acetates ; IFNG protein, mouse ; Neoplasm Proteins ; Interferon-gamma (82115-62-6) ; Acetate-CoA Ligase (EC 6.2.1.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-05-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.04.022
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Article ; Online: Mitochondrial Priming by CD28.

Klein Geltink, Ramon I / O'Sullivan, David / Corrado, Mauro / Bremser, Anna / Buck, Michael D / Buescher, Joerg M / Firat, Elke / Zhu, Xuekai / Niedermann, Gabriele / Caputa, George / Kelly, Beth / Warthorst, Ursula / Rensing-Ehl, Anne / Kyle, Ryan L / Vandersarren, Lana / Curtis, Jonathan D / Patterson, Annette E / Lawless, Simon / Grzes, Katarzyna /

Qiu, Jing / Sanin, David E / Kretz, Oliver / Huber, Tobias B / Janssens, Sophie / Lambrecht, Bart N / Rambold, Angelika S / Pearce, Edward J / Pearce, Erika L

Cell

2017 Volume 171, Issue 2, Page(s) 385–397.e11

Abstract: T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently ... ...

Abstract	T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.
MeSH term(s)	Animals ; CD28 Antigens/metabolism ; Carnitine O-Palmitoyltransferase ; Enzyme Inhibitors/pharmacology ; Epoxy Compounds/pharmacology ; Humans ; Interleukin-15/immunology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Stress, Physiological ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	CD28 Antigens ; Enzyme Inhibitors ; Epoxy Compounds ; Interleukin-15 ; Receptors, Antigen, T-Cell ; CPT1A protein, human (EC 2.3.1.21) ; CPT1B protein, mouse (EC 2.3.1.21) ; Carnitine O-Palmitoyltransferase (EC 2.3.1.21) ; etomoxir (MSB3DD2XP6)
Language	English
Publishing date	2017-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2017.08.018
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