Switching off immunity in health and disease

Summary

Immune activation, for example during an infection, is followed by feedback inhibition which dampens down the response. A failure to activate immunity results in overwhelming infection; equally, an inability to halt the immune response results in pathological inflammation and sometimes autoimmunity. We are interested in the molecular mechanisms used by the immune system to halt the response. In particular, we are interested in the action of immunosuppressive cytokines (such as TGF-beta and IL-10) and how anti-inflammatory drugs (such as steroids) mimic the action of these cytokines.

The project will use molecular and cellular techniques to define the signalling pathways used by immunosuppressive molecules to regulate immunity and how these pathways are modulated in human cancer and inflammation. The project will focus on the action of inhibitory molecules on natural killer (NK) cells and cytotoxic T cells, comparing cytokines and drugs for their ability to regulate immune activity. Tumours often exploit these pathways to inhibit anti-tumour immunity. Defining the mechanisms operating in cancer will enable the design of therapeutic strategies that will help to restore anti-tumor immunity.

References

1. Holmes TD, Wilson EB, Black EVI, Benest AV, Vaz C, Tan B, Tanavde VM, Cook GP (2014) Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT. Proc Natl Acad Sci USA 111(52):E5688-96.
2. Brownlie RJ, Garcia C, Ravasz M, Zehn D, Salmond RJ, Zamoyska R. 2017. Resistance to TGFβ suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22. Nat. Commun. 8(1):1343.
3. Wilson EB, El-Jawhari JJ, Neilson AL, Hall GD, Melcher AA, Meade JL and Cook GP (2011) Human tumour immune evasion via TGF-b blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS One 6:e22842.

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