Session Speaker

CD4-Mediated Activation of Human Regulatory T Cells and its Potential for Drug Development
Christian Becker, Christian Taube, Tobias Bopp, Christoph Becker, Jan Kubach, Sebastian Reuter, Nina Dehzad, Kurt Reifenberg, Franz-Joseph Schneider, Edgar Schmitt and Helmut Jonuleit
Germany


Because of their unique ability to actively suppress imbalanced immune responses, naturally occurring CD4+CD25+ regulatory T cells (Tregs) represent a important target in development of novel drugs that induce or restore immunological tolerance. Based on the established model of tolerance induction by anti-CD4 mAb in animal models, we explored the functional consequences of CD4 engagement on human Tregs. We identified an anti-CD4 antibody (BF-5) that fully activates the suppressive function of Tregs (1) which is now in clinical testing as BT-061. Furthermore, an additional CD4-binding protein, the HIV-1 envelope glycoprotein gp120, is also a potent Treg activator by the same mechanism. CD4-mediated Treg activation induces a strong production of the second messenger cyclic adenosine monophosphate (cAMP), an essential molecule of Treg activity (2). Evaluation of our results in a preclinical xenogeneic graft versus host (GvH-) model in vivo showed that a single dose of gp120 prevents all detectable GvHD symptoms in a Treg and cAMP dependent manner (3).

Our results disclose CD4 as an attractive target to harness the suppressive potential of Tregs. CD4-mediated Treg activation offers an exciting opportunity to prevent or ameliorate unwanted immune reactions in patients with allergy, autoimmune disorders or after transplantation.
First author is supported by the German Research Foundation (grant BE 3685/1-1).

References:

1. Becker, C., et al. 2007. CD4-mediated functional activation of human CD4+CD25+ regulatory T cells. Eur. J. Immunol. 37:1217-1223.
2. Bopp,T., C.Becker et al. 2007. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204:1303-1310.
3. Becker,C. et al. 2009. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells. Blood.