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Vitamin D and immunometabolism


Project Description

Vitamin D has potent anti-inflammatory and antibacterial immune effects. Indeed, it plays a key role in regulating normal inflammatory immune responses, as innate immune cells such as macrophages and dendritic cells convert vitamin D to its active form (1,25(OH)VitD3), which controls both innate inflammatory function, as well as that of powerful adaptive immune cells such as T cells and B cells. Better understanding of how this endogenous immune regulator works will undeniably contribute to the development of novel anti-inflammatory therapies, as well as providing a mechanistic basis for vitamin D-based therapies across a spectrum of inflammatory and autoimmune diseases.

In the last five years we have discovered that immune cells dramatically alter their metabolism during an immune response, which critically drives their inflammatory functionality through bioenergetic, transcriptional and translational pathways. Novel data from our lab indicate that 1,25(OH)VitD3 significantly impacts the metabolic reprogramming of immune cells, and this may be critical to the anti-inflammatory effects of vitamin D. Future projects will further investigate the metabolic effects of 1,25(OH)VitD3 on immune cells, using a variety of immunological techniques, as well as in-depth analyses of cellular metabolism.

Planned studies will investigate how 1,25(OH)VitD3 controls metabolic reprogramming in human innate immune cells (monocytes, macrophages, dendritic cells) to regulate their inflammatory potential, following differentiation and activation of immune cells in vitro in absence or presence of 1,25(OH)VitD3. Experiments will include analysis of immune cell phenotype using techniques including flow cytometry, ELISA and quantitative PCR. Cellular metabolism will be investigated using tools such as fluorescent nutrient analogues, mitochondrial dyes, measurement of oxygen consumption and in-depth, mass-spectrometry based metabolic tracing of isotope-labelled nutrients. Specific metabolic pathways will be linked to defined immunological phenotypes and inflammatory functions using established pharmacological tools.

The overall aim of the project is to define how 1,25(OH)VitD3 controls innate immune cell inflammatory potential by subverting metabolic reprogramming in macrophages and dendritic cells. Studies will build on preliminary data to investigate how altered innate cell metabolism impacts the induction of adaptive immune responses. It is already established that 1,25(OH)VitD3-primed antigen presenting cells (APCs) have reduced capacity to stimulate T and B lymphocytes, due to decreased expression of MHC, co-stimulatory molecules and inflammatory cytokines. However, the exciting concept that APC-derived metabolites may act as a novel ‘4th signal’ in the immune synapse –and furthermore that 1,25(OH)VitD3 may subvert this signal to control T cell inflammatory function– remains to be explored and will form the main objective of this proposed project.

Planned experiments will be carried out between the laboratories of Professor Martin Hewison and Dr Sarah Dimeloe, in conjunction with existing PhD students and laboratory technicians (Prof. Hewison’s lab currently has a postdoc fellow; 3 current PhD students, and a clinical fellow; Dr Dimeloe’s lab has a post-doctoral fellow and research technician). Existing expertise will be available to learn how to isolate and culture human immune cells from peripheral blood samples, and how to stimulate these cells in vitro. Prof. Hewison’s lab has specific expertise in innate immune cell biology and analyses, whereas Dr Dimeloe has extensive experience of T cell techniques. Complementary metabolic analyses will be carried out across the two laboratories.

Person Specification
Applicants should have a strong background in cell biology, and preferably with experience of immune cell culture and analysis of gene expression. They should have a commitment to immunology, inflammation or metabolism research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biosciences, Medical Sciences or Immunology.

Informal enquiries should be directed to Professor Martin Hewison, email

To be considered for this studentship, please send the following documents to Viktorija Ziabliceva, email :
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

Self-funded applications only.

References

Muñoz Garcia A, Kutmon M, Eijssen L, Hewison M, Evelo CT, Coort SL. Pathway analysis of transcriptomic data shows immunometabolic effects of vitamin D. J Mol Endocrinol. 2018 Feb;60(2):95-108. doi: 10.1530/JME-17-0186.

Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014 Apr 21;5:151. doi: 10.3389/fphys.2014.00151. eCollection 2014. Review. PubMed PMID: 24795646; PubMed Central PMCID: PMC4000998.

Dimeloe S, Burgener AV, Grählert J, Hess C. T-cell metabolism governing activation, proliferation and differentiation; a modular view. Immunology. 2017 Jan;150(1):35-44. doi: 10.1111/imm.12655.

Dimeloe S, Mehling M, Frick C, Loeliger J, Bantug GR, Sauder U, Fischer M, Belle R, Develioglu L, Tay S, Langenkamp A, Hess C. The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions. J Immunol. 2016 Jan 1;196(1):106-14. doi: 10.4049/jimmunol.1501766.

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