Hoffmann et al. (2004) documented up to 40,000-fold expansion in vitro by repeatedly stimulating with CD3 and CD28 and high dose interleukin 2. While using this technique significantly inhibits graft-versus-host disease (GVHD) as well as allo- and auto-immunity (Taylor et al., 2002; Xia et al., 2006), the inhibitory effect is more pronounced when antigen-specific Tregs are administered (Masteller et al., 2005; Trenado et al., 2006; Nagahama et al., 2007; Zeng et al., 2009; Brennan et al., 2011). Here, CD28 is linked to graft versus host disease.