University of Dundee

China Scholarship Council PhD programme: Regulation of anti-viral T cell immune responses by SIKs

The School of Life Sciences at the University of Dundee, joint with the China Scholarship Council (CSC), is proud to be able to offer a scholarship programme for postgraduate research students. The scholarship covers all tuition fees and research fees and provides living expenses and one return flight ticket to successful candidates. There are up to 5 scholarships of 4 years duration available.

 

Project Description

 

T cells play critical roles in the host immune response to infection by respiratory viruses.  This involves both killing of infected cells by CD8+ve cytotoxic T cells as well as control of immune responses by CD4+ve helper T cells.   This project will look at how a group of mammalian kinases, referred to as SIKs, regulate the T cell’s response following viral infection.  SIKs comprise a family of 3 protein kinases, of which SIK2 and 3 are the predominant isoforms T cells.  Previously we have identified important immunomodulatory roles for SIK2 and 3 in the innate immune system, where SIKs promote an anti-inflammatory pro-resolution phenotype.  Their role in adaptive immunity is however less well understood.  Double knockout of both SIK2 and 3 impacts T cell development in the thymus and initial data indicates that SIK inhibition in peripheral T cells blocks interferon gamma production from mature T cells.  In addition, activation of CD8 and CD4 T cells is able to significantly upregulate SIK3 levels.  Despite this, we do not understand the molecular targets of SIKs in T cells or their full impact on T cell function.  To address this the project will use a combination of SIK2 and 3 knockout mice in combination with mass spectrometry to determine how loss of SIK activity affects T cell function following viral infection.  Recent advances in mass spectrometry mean it is now possible to obtain detailed and accurately quantified proteomes from relatively small numbers of cells.  Using DIA methodology, the proteomes of both CD8 and CD4 T cells will quantified and comparisons between different genotypes and infected states used to map the intracellular processes controlled by SIKs.  Phospho-proteomic analysis will be used in parallel to determine proteins directly phosphorylated by SIKs.  Together this will increase our understanding of T cell immune responses and allow the evaluation of SIKs as potential targets for immunomodulatory drugs. 

 

1) MacKenzie et al, 2013 PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol. 2013, 190(2):565-77. PMID: 23241891  

 

2) Darling et al, 2017, Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. Biochem J. 474(4):521-537. PMID: 27920213 

 

3) Howden et al, 2019, Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation.  Nat Immunol. 20(11):1542-1554. PMID: 31591570