Overview

My research program aims to better understand how the immune system can be used to treat childhood diseases. In children with cancer, the immune system is no longer able to rid the body of cancerous cells. In children with autoimmune diseases the immune system gets rid of healthy cells of the body. We are particularly interested in the metabolism of immune cells. Metabolism consists of all the chemical processes that occur within a living organism that maintain life. In immune cells, this means that building blocks (metabolites) need to be brought in to allow the duplication of a cell by making all crucial parts of new cells. In fast growing immune cells this is especially demanding, since they need to duplicate themselves very rapidly to protect against attacks on the normal function of our bodies by, for instance, infections or cancer. This requires a variety of building blocks, and a lot of energy. For this process, cells can acquire these building blocks from their environment, or make them via intricate biochemical pathways. When the right building blocks are not available, immune cells fail to increase in numbers and cannot perform their job.

We use biochemical and metabolomic techniques to understand what fuel is needed for immune cell function, and how immune cells sense the fuel that is available in their environment.

By closely collaborating with Clinicians and Clinician scientists at BCCHR we are aiming to apply the findings to design better treatments for children with immune related diseases.

Publications

Transsulfuration, minor player or crucial for cysteine homeostasis in cancer
Trends in Cell Biology
Zhang, H.-F. and Klein Geltink, R.I. and Parker, S.J. and Sorensen, P.H.
DOI: 10.1016/j.tcb.2022.02.009
2022

PTEN is required for human Treg suppression of costimulation
bioRxiv
Lam, A.J. and Haque, M. and Ward-Hartstonge, K.A. and Uday, P. and Wardell, C.M. and Gillies, J.K. and Speck, M. and Mojibian, M. and Klein Geltink, R.I. and Levings, M.K.
DOI: 10.1101/2022.03.06.483188
2022

A low-sugar diet enhances Drosophila body size in males and females via sex-specific mechanisms
Development (Cambridge, England)
Millington, J.W. and Biswas, P. and Chao, C. and Xia, Y.H. and Wat, L.W. and Brownrigg, G.P. and Sun, Z. and Basner-Collins, P.J. and Klein Geltink, R.I. and Rideout, E.J.
DOI: 10.1242/dev.200491
2022

Executive CoAching unleashes Tc22 anti-tumor capacity
Science immunology
Klein Geltink, R.I. and Pillai, A.
DOI: 10.1126/sciimmunol.abn9190
2022

Metabolomic identification of a-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease
Blood
Subburaj, D. and Ng, B. and Kariminia, A. and Abdossamadi, S. and Lauener, M. and Nemecek, E.R. and Rozmus, J. and Kharbanda, S. and Kitko, C.L. and Lewis, V.A. and Schechter-Finklestein, T. and Jacobsohn, D.A. and Harris, A.C. and Pulsipher, M.A. and Bittencourt, H. and Choi, S.W. and Caywood, E.H. and Kasow, K.A. and Bhatia, M. and Oshrine, B.R. and Coulter, D. and Chewning, J.H. and Joyce, M. and Pawlowska, A.B. and Megason, G.C. and Lawitschka, A. and Ostroumov, E. and Klein Geltink, R. and Cuvelier, G.D.E. and Schultz, K.R.
DOI: 10.1182/blood.2021013244
2022

Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.
Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.2023752118
PubMed: 34161266
06/2021

Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.
Cancer discovery
DOI: 10.1158/2159-8290.cd-20-1690
PubMed: 34021002
05/2021

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.
Cell metabolism
DOI: 10.1016/j.cmet.2020.11.003
PubMed: 33264603
12/2020

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection.
PLoS pathogens
Montes de Oca M and de Labastida Rivera F and Winterford C and Frame TCM and Ng SS and Amante FH and Edwards CL and Bukali L and Wang Y and Uzonna JE and Kuns RD and Zhang P and Engwerda CR
DOI: 10.1371/journal.ppat.1008994
PubMed: 33049000
10/2020

EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism.
Genes & development
Ramamoorthy S and Kometani K and Herman JS and Bayer M and Boller S and Edwards-Hicks J and Ramachandran H and Li R and Klein-Geltink R and Pearce EL and Grün D and Grosschedl R
DOI: 10.1101/gad.340216.120
PubMed: 33004416
10/2020

Triacylglycerol synthesis enhances macrophage inflammatory function.
Nature communications
Castoldi A and Monteiro LB and van Teijlingen Bakker N and Sanin DE and Rana N and Corrado M and Cameron AM and Hässler F and Matsushita M and Caputa G and Klein Geltink RI and Pearce EJ
DOI: 10.1038/s41467-020-17881-3
PubMed: 32796836
08/2020

Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy.
Nature metabolism
Klein Geltink RI and Edwards-Hicks J and Apostolova P and O'Sullivan D and Sanin DE and Patterson AE and Puleston DJ and Ligthart NAM and Buescher JM and Grzes KM and Kabat AM and Pearce EL
DOI: 10.1038/s42255-020-0256-z
PubMed: 32747793
08/2020

Triacylglycerol synthesis enhances macrophage inflammatory function
Castoldi A and Monteiro LB and van Teijlingen Bakker N and Sanin DE and Rana N and Corrado M and Cameron AM and Hässler F and Matsushita M and Caputa G and Klein Geltink RI and Pearce EJ
DOI: 10.1101/2020.02.03.932079
02/2020

The metabolic tug of war between HIV and T cells
Nature Metabolism
Ramon I. Klein Geltink
DOI: 10.1038/s42255-019-0091-2
07/2019

The importance of methionine metabolism
eLife
Ramon I Klein Geltink and Erika L Pearce
DOI: 10.7554/elife.47221
05/2019

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation.
Cell metabolism
Puleston DJ and Buck MD and Klein Geltink RI and Kyle RL and Caputa G and O'Sullivan D and Cameron AM and Castoldi A and Musa Y and Kabat AM and Zhang Y and Flachsmann LJ and Field CS and Pearce EL
DOI: 10.1016/j.cmet.2019.05.003
PubMed: 31130465
05/2019

Acetate Promotes T Cell Effector Function during Glucose Restriction.
Cell reports
Qiu J and Villa M and Sanin DE and Buck MD and O'Sullivan D and Ching R and Matsushita M and Grzes KM and Winkler F and Chang CH and Curtis JD and Kyle RL and Van Teijlingen Bakker N and Pearce EL
DOI: 10.1016/j.celrep.2019.04.022
PubMed: 31091446
05/2019

Establishment of a transgenic mouse to model ETV7 expressing human tumors
Transgenic Research
DOI: 10.1007/s11248-018-0104-z
02/2019

T cell activation: The importance of methionine metabolism
eLife
Geltink, R.I.K. and Pearce, E.L.
DOI: 10.7554/eLife.47221
2019

A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
Nature Communications
Piragyte, I. and Clapes, T. and Polyzou, A. and Klein Geltink, R.I. and Lefkopoulos, S. and Yin, N. and Cauchy, P. and Curtis, J.D. and Klaeylé, L. and Langa, X. and Beckmann, C.C.A. and Wlodarski, M.W. and Müller, P. and Van Essen, D. and Rambold, A. and Kapp, F.G. and Mione, M. and Buescher, J.M. and Pearce, E.L. and Polyzos, A. and Trompouki, E.
DOI: 10.1038/s41467-018-05311-4
2018

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2
Immunity
Sanin, D.E. and Matsushita, M. and Klein Geltink, R.I. and Grzes, K.M. and van Teijlingen Bakker, N. and Corrado, M. and Kabat, A.M. and Buck, M.D. and Qiu, J. and Lawless, S.J. and Cameron, A.M. and Villa, M. and Baixauli, F. and Patterson, A.E. and Hässler, F. and Curtis, J.D. and O'Neill, C.M. and O'Sullivan, D. and Wu, D. and Mittler, G. and Huang, S.C.-C. and Pearce, E.L. and Pearce, E.J.
DOI: 10.1016/j.immuni.2018.10.011
2018

Unraveling the Complex Interplay between T Cell Metabolism and Function
Annual Review of Immunology
Geltink, R.I.K. and Kyle, R.L. and Pearce, E.L.
DOI: 10.1146/annurev-immunol-042617-053019
2018

ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer
Science Advances
Harwood, F.C. and Klein Geltink, R.I. and O?Hara, B.P. and Cardone, M. and Janke, L. and Finkelstein, D. and Entin, I. and Paul, L. and Houghton, P.J. and Grosveld, G.C.
DOI: 10.1126/sciadv.aar3938
2018

Caught in the cROSsfire: GSH Controls T Cell Metabolic Reprogramming
Immunity
Klein Geltink, R.I. and O'Sullivan, D. and Pearce, E.L.
DOI: 10.1016/j.immuni.2017.03.022
2017

Mitochondrial Priming by CD28
Cell
Klein Geltink, R.I. and O'Sullivan, D. and Corrado, M. and Bremser, A. and Buck, M.D. and Buescher, J.M. and Firat, E. and Zhu, X. and Niedermann, G. and Caputa, G. and Kelly, B. and Warthorst, U. and Rensing-Ehl, A. and Kyle, R.L. and Vandersarren, L. and Curtis, J.D. and Patterson, A.E. and Lawless, S. and Grzes, K. and Qiu, J. and Sanin, D.E. and Kretz, O. and Huber, T.B. and Janssens, S. and Lambrecht, B.N. and Rambold, A.S. and Pearce, E.J. and Pearce, E.L.
DOI: 10.1016/j.cell.2017.08.018
2017

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
Cell
Buck, M.D. and O'Sullivan, D. and Klein~Geltink, R.I. and Curtis, J.D. and Chang, C.-H. and Sanin, D.E. and Qiu, J. and Kretz, O. and Braas, D. and van~der~Windt, G.J.W. and Chen, Q. and Huang, S.C.-C. and O'Neill, C.M. and Edelson, B.T. and Pearce, E.J. and Sesaki, H. and Huber, T.B. and Rambold, A.S. and Pearce, E.L.
DOI: 10.1016/j.cell.2016.05.035
2016

High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells
Leukemia Research
Numata, M. and Yener, M.D. and Ekmek?i, S.S. and Aydin, M. and Grosveld, G. and Cardone, M. and Terranova, S. and Geltink, R.K. and Özbek, U. and Öz?elik, E. and Güle?, T. and Anak, S. and Karaman, S. and Öztürk, G. and Akbiyik, M. and Kandilci, A.
DOI: 10.1016/j.leukres.2015.05.013
2015

Zebrafish etv7 regulates red blood cell development through the cholesterol synthesis pathway
DMM Disease Models and Mechanisms
Quintana, A.M. and Picchione, F. and Geltink, R.I.K. and Taylor, M.R. and Grosveld, G.C.
DOI: 10.1242/dmm.015123
2014

PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis
Neoplasia (United States)
Marshall, A.D. and Picchione, F. and Klein Geltink, R.I. and Grosveld, G.C.
DOI: 10.1593/neo.121888
2013

MN1 overexpression is an important step in the development of inv(16) AML
Leukemia
Carella, C. and Bonten, J. and Sirma, S. and Kranenburg, T.A. and Terranova, S. and Klein-Geltink, R. and Shurtleff, S. and Downing, J.R. and Zwarthoff, E.C. and Liu, P.P. and Grosveld, G.C.
DOI: 10.1038/sj.leu.2404778
2007

Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
Blood
Schreurs, M.W.J. and Hermsen, M.A.J.A. and Geltink, R.I.K. and Scholten, K.B.J. and Brink, A.A.T.P. and Kueter, E.W.M. and Tijssen, M. and Meijer, C.J.L.M. and Ylstra, B. and Meijer, G.A. and Hooijberg, E.
DOI: 10.1182/blood-2004-09-3742
2005

Research

The role of metabolism in regulation of function in immune cells
My lab aims to better understand the role of metabolism in regulation of function in immune cells. We aim to expand our understanding of the role of metabolism in the dysfunction of immune cells in cancer, and their hyperactivation in autoimmune conditions.

When cells are confronted with changing environments they have to adapt to their new surroundings to maintain cellular function. This adaptation is especially relevant for immune cells that move throughout the body and encounter different levels of metabolites and nutrients in the blood, tissues or tumours they traverse. The availability of nutrients influences immune cell metabolism, but having a metabolite available does not mean a cell will necessarily use it.

Cellular metabolism consists of an interconnected network that is influenced by at least 4 factors which we aim to better understand:

1. Metabolite availability
How do immune cells sense their nutritional environment, and how are these signals transmitted?

2. Metabolite transport into the cell
How are metabolite transporters regulated during immune cell activation?

3. Metabolic enzyme expression
Metabolic enzymes are often considered "household genes" for control experiments. How is activity of these enzymes modulated?

4. Availability of enzyme cofactors
Most, if not all, metabolic enzymes are dependent on substrate and cofactors. We are interested in the sensing of cofactor status and their effects on metabolic pathway flux.

Not all immune cells use the same metabolic pathways even if metabolites are abundant, transporters and enzymes are expressed, and cofactors are available. The response can be regulated by growth factors, cytokines, or immune cell receptor signaling, and we aim to better understand the signals that provide the instructions for which metabolic pathway to use.

Research Group Members

Anne-Sophie Archambault, Postdoctoral Fellow
Sara Niyyati, Summer Student
Juhee Oh, Doctoral Student
Annette Patterson, Lab Manager
Clara Schumacher
Terri Ser, Masters Student
Lucas Starchuk, Graduate Student
Erin Tanaka
Pattie Ye, Graduate Student
Annie Zhou, Summer Student