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.


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

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

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

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

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

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

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

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

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

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

Establishment of a transgenic mouse to model ETV7 expressing human tumors
Transgenic Research

A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
Nature Communications
DOI: 10.1038/s41467-018-05311-4

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2
DOI: 10.1016/j.immuni.2018.10.011

Unraveling the Complex Interplay between T Cell Metabolism and Function
Annual Review of Immunology
DOI: 10.1146/annurev-immunol-042617-053019

ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer
Science Advances
DOI: 10.1126/sciadv.aar3938

Caught in the cROSsfire: GSH Controls T Cell Metabolic Reprogramming
DOI: 10.1016/j.immuni.2017.03.022

Mitochondrial Priming by CD28
DOI: 10.1016/j.cell.2017.08.018

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
DOI: 10.1016/j.cell.2016.05.035

High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells
Leukemia Research
DOI: 10.1016/j.leukres.2015.05.013

Zebrafish etv7 regulates red blood cell development through the cholesterol synthesis pathway
DMM Disease Models and Mechanisms
DOI: 10.1242/dmm.015123

PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis
Neoplasia (United States)
DOI: 10.1593/neo.121888

MN1 overexpression is an important step in the development of inv(16) AML
DOI: 10.1038/sj.leu.2404778

Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
DOI: 10.1182/blood-2004-09-3742


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

Sara Niyyati, Summer Student
Juhee Oh, Doctoral Student
Janice Pang
Annette Patterson, Lab Manager
Terri Ser, Summer Student
Lucas Starchuk, Graduate Student
Erin Tanaka
Pattie Ye, Graduate Student