Determining important novel mechanisms that regulate T-cell-mediated immune responses.

The immune system must be capable of rapidly responding to pathogens, but be tightly regulated to prevent self-harmful immune responses against our own tissues to maintain health. T-cells are crucial immune cells that fight a variety of pathogens, but are can become activated to attack our own bodies and disrupt homoeostasis. Thus, identifying important mechanisms that regulate T-cells is crucial in understanding how the immune system is regulated to promote health.
Recent work in the Travis lab has identified a crucial molecule, expressed by antigen presenting dendritic cells (DCs) and immunosuppressive regulatory T-cells (Tregs) that is vital in regulation of T-cell responses. Thus, expression of the cell surface receptor integrin alphav beta8 by both DCs and Tregs is fundamental in promoting T-cell health 1-3, with expression of the integrin by DCs important in regulating responses to infection. Thus, how integrin alphav beta8 is regulated, and the molecular pathways downstream of the integrin that are important in controlling immune cell behaviour and T-cell responses are crucial, but unanswered, questions.
Using the bioinformatics expertise of Schwartz, publicly available microarray datasets (www.immgen.com) will be interrogated to identify gene networks that are significantly correlated with expression of integrin alphav beta8. The functional importance of candidate genes identified from the bioinformatics screen will then be tested using a variety of in vitro and in vivo immunological assays in mice (Travis), using knockout mouse models and/or CRISPR-mediated knockdown of targets of interest in primary cells. Initial focus of experiments will be on effects on T-cell responses shown to be regulated by integrin aphav beta8 (i.e. induction of suppressive Tregs, inhibition of Th2 responses, induction of Th17 responses). Interesting findings in mice will then be translated into humans, looking at candidate gene function by CRISPR-mediated knockdown in primary human immune cells from healthy individuals and patients with inflammation. Thus, the project will provide a unique training opportunity combining computational biology and immunology, identifying crucial mechanisms that are important in T-cell responses keeping us healthy.

The specific aims of the project are to:

1. Determine gene signatures/pathways that are significantly associated with expression of integrin alphav beta8, via bioinformatic modelling of extensive publicly available microarray data for immune cells.
2: Determine the functional importance of associated gene pathways in regulation of T-cell responses using murine models
3: Determine the functional importance of genes identified in aims 1 and 2 in primary human immune cells.

The project brings together experts in immune cell biology (Travis) and bioinformatics (Schwartz), to determine novel pathways by which T cell responses are controlled. The project will provide important training in both computational biology, and how hypotheses generated from bioinformatics can be directly tested experimentally. The project will therefore directly address the BBSRC's goal for researchers to be able to apply computational techniques to biological data. Such skills will put the student in an extremely strong position after their PhD, given the massive expansion in big genomic and proteomic datasets that are currently underutilised by general biologists due to their difficulty to navigate for people without bioinformatics training.