Abstract
Unrestricted somatic stem cells (USSC) have the potential to differentiate into tissues derived from all three germinal layers and therefore hold promise for use in regenerative therapies. Furthermore, they have haematopoietic stromal activity, a characteristic that may be exploited to enhance haematopoietic engraftment. Both applications may require USSC to be used in an allogeneic, HLA-mismatched setting. We have therefore studied their in vitro interaction with cellular immunity. USSC showed no allostimulatory activity and caused only minimal inhibition of allogeneic T-cell responses. However, following pre-stimulation with IFNgamma and TNFalpha, they inhibited T-cell proliferation in an indoleamine 2, 3-dioxygenase-dependent manner and suppressed graft-versus-host type reactions. In addition, USSC inhibited DC maturation and function. This inhibition was overridden by stronger DC maturation signals provided by IL-1beta, IL-6, PGE(2) and TNFalpha compared to TNFalpha alone. Pre-stimulation of USSC with IFNgamma and TNFalpha had a similar effect: Inhibition of DC maturation was no longer observed. Thus, USSC are conditionally immunosuppressive, and IFNgamma and TNFalpha constitute a switch, which regulates their immunological properties. They either suppress T-cell responses in the presence of both cytokines or in their absence block DC differentiation and function. These activities may contribute to fine-tuning the immune system especially at sites of tissue damage in order to ensure appropriate differentiation of USSC and subsequent tissue repair. Therapeutically, they may help to protect USSC and possibly their progeny from immune rejection.