Life Sciences Research for Lifelong Health

Sarah Ross

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.

Latest Publications

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

Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8(+) T Cells.
Ross SH, Rollings C, Anderson KE, Hawkins PT, Stephens LR, Cantrell DA

Interleukin-2 (IL-2) is a fundamental cytokine that controls proliferation and differentiation of T cells. Here, we used high-resolution mass spectrometry to generate a comprehensive and detailed map of IL-2 protein phosphorylations in cytotoxic T cells (CTL). The data revealed that Janus kinases (JAKs) couple IL-2 receptors to the coordinated phosphorylation of transcription factors, regulators of chromatin, mRNA translation, GTPases, vesicle trafficking, and the actin and microtubule cytoskeleton. We identified an IL-2-JAK-independent SRC family Tyr-kinase-controlled signaling network that regulates ∼10% of the CTL phosphoproteome, the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), and the activity of the serine/threonine kinase AKT. These data reveal a signaling framework wherein IL-2-JAK-controlled pathways coordinate with IL-2-independent networks of kinase activity and provide a resource toward the further understanding of the networks of protein phosphorylation that program CTL fate.

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Immunity, , 1097-4180, , 2016

PMID: 27566939

 

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

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