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.
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Metabolic and nutrient-sensing pathways play an important role in controlling the efficacy of effector T cells. Oxygen is a critical regulator of cellular metabolism. However, during immune responses T cells must function in oxygen-deficient, or hypoxic, environments. Here, we used high resolution mass spectrometry to investigate how the proteome of primary murine CD8 cytotoxic T lymphocytes (CTLs) is reconfigured in response to hypoxia . We identified and quantified over 7,600 proteins and discovered that hypoxia increased the abundance of a selected number of proteins in CTLs. This included glucose transporters, metabolic enzymes, transcription factors, cytolytic effector molecules, checkpoint receptors and adhesion molecules. While some of these proteins may augment the effector functions of CTLs, others may limit their cytotoxicity. Moreover, we determined that hypoxia could inhibit IL-2-induced proliferation cues and antigen-induced pro-inflammatory cytokine production in CTLs. These data provide a comprehensive resource for understanding the magnitude of the CTL response to hypoxia and emphasise the importance of oxygen-sensing pathways for controlling CD8 T cells. Additionally, this study provides new understanding about how hypoxia may promote the effector function of CTLs, while contributing to their dysfunction in some contexts.
Personalized medicines require understanding the molecular causes of disease. In this issue of Immunity, Gruber et al. reveal that a gain-of-function JAK1 genetic variant results in a mutant protein with mosaic expression that drives multi-organ immune dysregulation via kinase dependent and independent mechanisms. The work highlights how biochemistry can inform therapies to resolve complex immune disorders.
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.