Matthew Taylor

Tel: +44 (0)131 651 3626
Email: Matthew.Taylor@ed.ac.uk

Street: Rm. 311A, Ashworth Building
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Biography

Background

1995 Research Assistant, Universtity of Glasgow

1996 Research Assistant, Universidade Federal de Minas Gerais, Brazil

1996-2000 PhD, University of Manchester

2000-2001 Post-Doctoral Fellow, University of British Columbia

2001-2006 Post-Doctoral Researcher, University of Edinburgh

2006-Present MRC Career Development Fellow, University of Edinburgh

The orchestration of a successful immune response requires a tight balance between mobilising a sufficient and correct effector response, whilst simultaneously regulating that response to prevent it becoming pathogenic. Helminth parasites excel at subverting this balance, using the host's own immune regulatory mechanisms to prevent effective immunity, resulting in immune suppression and chronic infection in the majority of individuals.

Aims:

The goals of my research are to use murine models of filariasis ( Litomosoides sigmodontis) and schistosomiasis (in collaboration with Andrew MacDonald, University of Edinburgh) to understand how T cell responses are positively and negatively regulated during helminth infections, and to develop therapeutic interventions allowing us to manipulate the regulatory/effector balance to restore protective immunity.

Background:

This project exploits the unique ability of the filarial parasite, Litomosoides sigmodontis, to develop a fully patent infection within inbred mouse strains. Susceptibility to filarial infection is controlled by two levels of T cell regulation:

by the rapid and preferential induction of a CD4 ⁺Foxp3 ⁺ regulatory T (Tr) cell response
by the development of an intrinsically hypo-responsive phenotype within the CD4 ⁺ effector T (Teff) cell population

We have published the first in vivo demonstration that helminth infection can be cleared and immunity restored by the removal of Tr cells, with evidence that Teff cell unresponsiveness can be reversed by the provision of appropriate co-stimulatory signals (Eg. GITR) or by the neutralisation of co-inhibitory signals (Eg. CTLA-4). ( Taylor et al. J. Immunol. 174: 4924 4933).

The Ongoing Project:

Do signals through T cell co-stimulatory/inhibitory pathways control the effector/regulatory balance, and can we manipulate these pathways to drive protective immunity? It is critical to understand why infection preferentially induces a regulatory response and one possibility is that filarial parasites suppress initial Teff cell priming (leading to hypo-responsiveness) and favour Tr cell priming. The positive and negative secondary signals received through co-stimulatory (e.g. CD28, GITR, ICOS, OX40) and co-inhibitory (e.g. CTLA-4, PD-1) molecules on the surface of the T cell play an important role in controlling the development of T cell responses. A lack of co-stimulation or bias towards co-inhibitory signals will impair immunity, leading to the hypothesis that the balance of secondary signals during priming will define whether regulatory or effector responses prevail.

We aim to manipulate co-stimulatory/inhibitory pathways during L. sigmodontis infection using a combination of agonistic and blocking monoclonal antibodies to dissect their role in the development of Tr cell responses, and in Teff cell unresponsiveness. The ultimate goal being to reverse regulation and induce a protective immune response.

As our work with L. sigmodontis develops we will extend our findings into the Schistosoma mansoni infection model, to ask whether successful treatments can be adapted to the treatment of phylogenetically distinct helminth infections. This will be performed in collaboration with Dr Andrew MacDonald (IIIR, University of Edinburgh).

Where are Tr cells primed, and with which cell types do they interact in vivo? Given the early dominance of the Tr cell response pertinent and fundamental questions arise: where is this response primed, how does it inhibit protective immunity, and through which cell type does it act? Recent evidence suggests that Foxp3 ⁺ Tr cell responses to self Ag are primed within the LN, and can act by inhibiting the priming of Teff cells ( Tang, Q., et al. 2006. Nat. Immunol. 7:83.). Interestingly, in contrast to in vitro studies, suppression did not appear to be through direct T-T cell interactions. How Foxp3 ⁺ Tr cells respond to challenge with foreign Ag is still relatively unknown, and L. sigmodontis provides a unique model in which to visualise a Tr cell response during a natural infection.

Using Foxp3 and IL-4 transgenic reporter mice we aim to visualise the priming of Tr and Th2 Teff cell responses during L. sigmodontis infection, and to ask whether the Tr and Teff cells interact in vivo. This will initially be developed using fluorescence confocal microscopy, with the aim of moving into real time 2-photon microscopy. This work will be performed in collaboration with Prof. Paul Garside (University of Strathclyde).