Life Sciences Research for Lifelong Health

Sarah Ross

Research Goals

  • Understanding how oxygen levels control post-translational modification of proteins to regulate signalling networks and protein complexes.
  • Determining how oxygen levels impact on many aspects of transcription and epigenetic control of gene expression in T cells.
  • Establishing how oxygen levels configure the immune response and the role of prolonged hypoxia in contributing to dysfunctional fate decisions in T cells.

Research Summary

T lymphocytes (a type of white blood cell, also called T cells) play a vital role in the adaptive immune responses that defend our bodies from invading pathogens and protect against the growth of cancer cells. The efficacy of T lymphocytes is determined by a combination of chemical cues and physical factors. T lymphocyte functions are guided by chemical signals like cytokines as well as factors including the nutrient levels of diseased tissues. Our aim is to determine how these factors impact on how well T lymphocytes can destroy diseased cells and clear infections. In particular, we are interested in understanding how low oxygen levels, or hypoxia, control the ability of T lymphocytes to perform their protective tasks.
In order to investigate this, we perform biochemical analyses of T lymphocytes grown in the lab as primary cultures to characterise how low oxygen environments impact on cellular processes, such as signalling and gene expression, that control T lymphocyte function. The results from these culture systems can then be used to examine and understand specific changes that T lymphocytes undergo during an immune response within the body.
Identifying how oxygen levels control T lymphocytes will improve our understanding of immune responses, and the molecules and processes that can cause T lymphocytes to function incorrectly. By understanding healthy and diseased T lymphocytes, this research aims to identify therapeutic approaches to rejuvenate declined immune function associated with ageing, uncover new strategies to treat autoimmune disorders and cancers and improve the effectiveness of existing immunotherapies.

Find out more about our research.

Latest Publications

Author Correction: Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.
Choy MK, Javierre BM, Williams SG, Baross SL, Liu Y, Wingett SW, Akbarov A, Wallace C, Freire-Pritchett P, Rugg-Gunn PJ, Spivakov M, Fraser P, Keavney BD

In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as 'TFP1' instead of 'TFPI'. This has now been corrected in both the PDF and HTML versions of the Article.

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Nature communications, 9, 2041-1723, 4792, 2018

PMID: 30420621

Signaling and Function of Interleukin-2 in T Lymphocytes.
Ross SH, Cantrell DA

The discovery of interleukin-2 (IL-2) changed the molecular understanding of how the immune system is controlled. IL-2 is a pleiotropic cytokine, and dissecting the signaling pathways that allow IL-2 to control the differentiation and homeostasis of both pro- and anti-inflammatory T cells is fundamental to determining the molecular details of immune regulation. The IL-2 receptor couples to JAK tyrosine kinases and activates the STAT5 transcription factors. However, IL-2 does much more than control transcriptional programs; it is a key regulator of T cell metabolic programs. The development of global phosphoproteomic approaches has expanded the understanding of IL-2 signaling further, revealing the diversity of phosphoproteins that may be influenced by IL-2 in T cells. However, it is increasingly clear that within each T cell subset, IL-2 will signal within a framework of other signal transduction networks that together will shape the transcriptional and metabolic programs that determine T cell fate.

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Annual review of immunology, 36, 1545-3278, 411-433, 2018

PMID: 29677473

Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs.
Rollings CM, Sinclair LV, Brady HJM, Cantrell DA, Ross SH

Interleukin-2 (IL-2) and Janus kinases (JAKs) regulate transcriptional programs and protein synthesis to promote the differentiation of effector CD8 cytotoxic T lymphocytes (CTLs). Using high-resolution mass spectrometry, we generated an in-depth characterization of how IL-2 and JAKs configure the CTL proteome to control CTL function. We found that IL-2 signaling through JAK1 and JAK3 (JAK1/3) increased the abundance of a key subset of proteins to induce the accumulation of critical cytokines and effector molecules in T cells. Moreover, IL-2 maintained the concentration of proteins that support core metabolic processes essential for cellular fitness. One fundamental insight was the dominant role for IL-2 in stimulating effector T cells to detect microenvironmental cues. IL-2-JAK1/3 signaling pathways thus increased the abundance of nutrient transporters, nutrient sensors, and critical oxygen-sensing molecules. These data provide key insights into how IL-2 promotes T cell function and highlight signaling mechanisms and transcription factors that integrate oxygen sensing to transcriptional control of CD8 T cell differentiation.

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Science signaling, 11, 1937-9145, , 2018

PMID: 29666307

Group Members

Latest Publications

Signaling and Function of Interleukin-2 in T Lymphocytes.

Ross SH, Cantrell DA

Annual review of immunology
36 1545-3278:411-433 (2018)

PMID: 29677473

Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs.

Rollings CM, Sinclair LV, Brady HJM

Science signaling
11 1937-9145: (2018)

PMID: 29666307

Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29.

Post A, Pannekoek WJ, Ross SH

Proceedings of the National Academy of Sciences of the United States of America
110 1091-6490:11427-32 (2013)

PMID: 23798437

Ezrin is required for efficient Rap1-induced cell spreading.

Ross SH, Post A, Raaijmakers JH

Journal of cell science
124 1477-9137:1808-18 (2011)

PMID: 21540295

Differential redox regulation within the PTP superfamily.

Ross SH, Lindsay Y, Safrany ST

Cellular signalling
19 0898-6568:1521-30 (2007)

PMID: 17346927

Stimulation of PI 3-kinase signaling via inhibition of the tumor suppressor phosphatase, PTEN.

Downes CP, Ross S, Maccario H

Advances in enzyme regulation
47 0065-2571:184-94 (2007)

PMID: 17343901

Substrate specificity and acute regulation of the tumour suppressor phosphatase, PTEN.

Downes CP, Perera N, Ross S

Biochemical Society symposium
0067-8694:69-80 (2007)

PMID: 17233581

Redox regulation of phosphatase function.

Leslie NR, Lindsay Y, Ross SH

Biochemical Society transactions
32 0300-5127:1018-20 (2004)

PMID: 15506952