Hexokinase 2 is dispensable for T cell-dependent immunity

Abstract Background T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the de...

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Main Authors: Manan M. Mehta, Samuel E. Weinberg, Elizabeth M. Steinert, Krishan Chhiba, Carlos Alberto Martinez, Peng Gao, Harris R. Perlman, Paul Bryce, Nissim Hay, Navdeep S. Chandel
Format: Article
Language:English
Published: BMC 2018-08-01
Series:Cancer & Metabolism
Subjects:
Online Access:http://link.springer.com/article/10.1186/s40170-018-0184-5
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spelling doaj-84278dafdee54bb999a4ec239b5afd5a2020-11-24T21:24:40ZengBMCCancer & Metabolism2049-30022018-08-016111810.1186/s40170-018-0184-5Hexokinase 2 is dispensable for T cell-dependent immunityManan M. Mehta0Samuel E. Weinberg1Elizabeth M. Steinert2Krishan Chhiba3Carlos Alberto Martinez4Peng Gao5Harris R. Perlman6Paul Bryce7Nissim Hay8Navdeep S. Chandel9Department of Medicine, Northwestern University Feinberg School of MedicineDepartment of Medicine, Northwestern University Feinberg School of MedicineDepartment of Medicine, Northwestern University Feinberg School of MedicineDepartment of Medicine, Northwestern University Feinberg School of MedicineDepartment of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of MedicineMetabolomics Core Facility, Northwestern University Robert H. Lurie Comprehensive Cancer CenterDepartment of Medicine, Northwestern University Feinberg School of MedicineDepartment of Medicine, Northwestern University Feinberg School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Illinois at ChicagoDepartment of Medicine, Northwestern University Feinberg School of MedicineAbstract Background T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia. Methods HK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression. Results We unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia. Conclusions HK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function.http://link.springer.com/article/10.1186/s40170-018-0184-5Hexokinase 2T cellsTregsLeukemiaColitisLCMV
collection DOAJ
language English
format Article
sources DOAJ
author Manan M. Mehta
Samuel E. Weinberg
Elizabeth M. Steinert
Krishan Chhiba
Carlos Alberto Martinez
Peng Gao
Harris R. Perlman
Paul Bryce
Nissim Hay
Navdeep S. Chandel
spellingShingle Manan M. Mehta
Samuel E. Weinberg
Elizabeth M. Steinert
Krishan Chhiba
Carlos Alberto Martinez
Peng Gao
Harris R. Perlman
Paul Bryce
Nissim Hay
Navdeep S. Chandel
Hexokinase 2 is dispensable for T cell-dependent immunity
Cancer & Metabolism
Hexokinase 2
T cells
Tregs
Leukemia
Colitis
LCMV
author_facet Manan M. Mehta
Samuel E. Weinberg
Elizabeth M. Steinert
Krishan Chhiba
Carlos Alberto Martinez
Peng Gao
Harris R. Perlman
Paul Bryce
Nissim Hay
Navdeep S. Chandel
author_sort Manan M. Mehta
title Hexokinase 2 is dispensable for T cell-dependent immunity
title_short Hexokinase 2 is dispensable for T cell-dependent immunity
title_full Hexokinase 2 is dispensable for T cell-dependent immunity
title_fullStr Hexokinase 2 is dispensable for T cell-dependent immunity
title_full_unstemmed Hexokinase 2 is dispensable for T cell-dependent immunity
title_sort hexokinase 2 is dispensable for t cell-dependent immunity
publisher BMC
series Cancer & Metabolism
issn 2049-3002
publishDate 2018-08-01
description Abstract Background T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia. Methods HK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression. Results We unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia. Conclusions HK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function.
topic Hexokinase 2
T cells
Tregs
Leukemia
Colitis
LCMV
url http://link.springer.com/article/10.1186/s40170-018-0184-5
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