Cargando…
Hexokinase 2 is dispensable for T cell-dependent immunity
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 developmen...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098591/ https://www.ncbi.nlm.nih.gov/pubmed/30140438 http://dx.doi.org/10.1186/s40170-018-0184-5 |
_version_ | 1783348507792375808 |
---|---|
author | Mehta, Manan M. Weinberg, Samuel E. Steinert, Elizabeth M. Chhiba, Krishan Martinez, Carlos Alberto Gao, Peng Perlman, Harris R. Bryce, Paul Hay, Nissim Chandel, Navdeep S. |
author_facet | Mehta, Manan M. Weinberg, Samuel E. Steinert, Elizabeth M. Chhiba, Krishan Martinez, Carlos Alberto Gao, Peng Perlman, Harris R. Bryce, Paul Hay, Nissim Chandel, Navdeep S. |
author_sort | Mehta, Manan M. |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0184-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6098591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-60985912018-08-23 Hexokinase 2 is dispensable for T cell-dependent immunity Mehta, Manan M. Weinberg, Samuel E. Steinert, Elizabeth M. Chhiba, Krishan Martinez, Carlos Alberto Gao, Peng Perlman, Harris R. Bryce, Paul Hay, Nissim Chandel, Navdeep S. Cancer Metab Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0184-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-17 /pmc/articles/PMC6098591/ /pubmed/30140438 http://dx.doi.org/10.1186/s40170-018-0184-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Mehta, Manan M. Weinberg, Samuel E. Steinert, Elizabeth M. Chhiba, Krishan Martinez, Carlos Alberto Gao, Peng Perlman, Harris R. Bryce, Paul Hay, Nissim Chandel, Navdeep S. Hexokinase 2 is dispensable for T cell-dependent immunity |
title | 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_short | Hexokinase 2 is dispensable for T cell-dependent immunity |
title_sort | hexokinase 2 is dispensable for t cell-dependent immunity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098591/ https://www.ncbi.nlm.nih.gov/pubmed/30140438 http://dx.doi.org/10.1186/s40170-018-0184-5 |
work_keys_str_mv | AT mehtamananm hexokinase2isdispensablefortcelldependentimmunity AT weinbergsamuele hexokinase2isdispensablefortcelldependentimmunity AT steinertelizabethm hexokinase2isdispensablefortcelldependentimmunity AT chhibakrishan hexokinase2isdispensablefortcelldependentimmunity AT martinezcarlosalberto hexokinase2isdispensablefortcelldependentimmunity AT gaopeng hexokinase2isdispensablefortcelldependentimmunity AT perlmanharrisr hexokinase2isdispensablefortcelldependentimmunity AT brycepaul hexokinase2isdispensablefortcelldependentimmunity AT haynissim hexokinase2isdispensablefortcelldependentimmunity AT chandelnavdeeps hexokinase2isdispensablefortcelldependentimmunity |