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Targeting TGF-β activation, likely the core mechanism of immunosuppression by human regulatory T cells. (TARG-SUP)
Start date: Apr 1, 2016, End date: Mar 31, 2021 PROJECT  FINISHED 

Regulatory T lymphocytes (Tregs) inhibit immune responses and are required to maintain immune tolerance. Tregs express membrane protein GARP, which displays latent TGF-β1 on the cell surface. Immunosuppression by human Tregs appears to require GARP-mediated activation of TGF-β1.My objectives are to unravel the molecular aspects of TGF-β1 activation by GARP and determine the functional importance of this process in physiological and pathological conditions where Tregs or other GARP-expressing cells are present. As this implies the development of new tools to modulate GARP-dependent TGF-β1 activation and Treg immunosuppression, we will also explore their potential for the treatment of immune-related human diseases, and notably cancer.More specifically, I will:- Derive antibodies that modulate GARP-mediated TGF-β1 production by human Tregs and perform structural analyses in the presence of these antibodies to identify tri-dimensional changes in GARP/TGF-β1 complexes that lead to the release of active TGF-β1.- Identify and characterize additional proteins implicated in TGF-β1 activation by human Tregs, as GARP is required but not sufficient for TGF-β1 activation by Tregs. - Determine the immunological and clinical impact of inhibitory anti-GARP mAbs on cancer in mice. We will derive anti-murine GARP mAbs. As an alternative, we will generate mutant mice expressing a chimeric mouse/human GARP that is recognized by anti-human GARP mAbs. The antibodies will be tested in tumour-bearing mice treated or not with other immunotherapies including vaccines or immunostimulatory antibodies.- Determine whether blocking anti-GARP mAbs improve immune responses to microbial vaccines or to chronic infections, as these represent important applications for transient inhibition of Treg activity in humans.- Analyse the expression and roles of GARP in non-Treg cells to better understand GARP functions, which remain largely unknown, and predict potential toxicities of anti-GARP mAbs.
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