Role of antigen-specificity for adoptive T-cell transfer (ACT)-based fungal therapy

Supervisors: Dietmar M.W. Zaiss, Gordon D. Brown

Project Description:

Fending off of pathogen infections while at the same time maintaining tissue homeostasis is a central function of the immune system. Nevertheless, the underlying mechanisms that balance pathogen clearance with wound repair remain largely unknown. Consequently, we are limited in therapeutic options for the prevention and treatment of infection-induced diseases.

CD4 T-cells are well-established regulators of local inflammation and we recently discovered that an evolutionary conserved signalling receptor, the Epidermal Growth Factor Receptor (EGFR), is expressed by CD4 T-cells. Activated CD4 T-cells use the expression of the EGFR to regulate local inflammation as well as their own functionality. We have shown that hetero-complexes between the EGFR and receptors of pro-inflammatory cytokines can be formed on CD4 T-cells. These hetero-complexes allow CD4 T-cells to respond in an antigen-independent way purely by being exposed to inflammatory cytokines.

In this project, we will utilize a fungal infection model in mice to establish, whether the immune system uses the formation of EGFR-dependent hetero-complexes to licence effector CD4 T-cells to express effector cytokines at the site of infection in an inflammation-induced, antigen-independent way. We will thereby rely on an adoptive T-cell transfer (ACT) model of in vitro differentiated Th17 from a transgenic mouse strain expressing a TCR specific for a fungus-derived antigen, and will measure to which extent EGFR expression by transferred CD4 T-cells influences the efficiency by which transferred T-cells can contribute to pathogen-clearance in MHC-II gene-deficient mice.

These experiments will educate us about the underlying mechanisms that separate the expansion of pathogen-specific CD4 T-cells from the execution of their effector function at the site of infection. Such knowledge may help us to develop novel ACT-based fungal treatments, in particular in the elderly.

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