Activation of alloreactive T cells by allogeneic nonprofessional antigenpresenting cells and interleukin-12 from bystander autologous professional antigenpresenting cells

Background. After solid organ transplantation most alloantigens are present ed to the recipient's immune system by normal tissue cells, which can be co nsidered to act as nonprofessional antigen-presenting cells (APC). It is we ll accepted that such nonprofessional APC fail to activate recipient restin g T cells due to their inability to deliver costimulatory activity. In our study, we tested a hypothesis that such costimulatory activity may be provi ded by "bystander" recipient professional APC. Methods. We set up mixed lymphocyte cultures (MLC) of purified T cell respo nders and T cell stimulator cells, the latter as nonprofessional APC carryi ng allogeneic MHC class I and II, and tested if responder-type autologous A PC could facilitate responder T cell proliferation. In this assay also the effects of anti-CD28 antibody and interleukin- (IL) 1 beta, IL-6, or IL-12 mediated costimulation on responder T cell proliferation and IL-2 productio n were investigated. Results. Autologous APC, i.e., monocytes, were found to facilitate the prol iferative response of resting T cells stimulated by allogeneic nonprofessio nal APC, IL-12 was identified as the most important costimulatory factor fo r induction of proliferation. IL-1 beta enhanced IL-2 production and prolif eration of allostimulated resting T cells but its presence was not essentia l. Although CD28 triggering alone was ineffective, this costimulatory pathw ay enhanced IL-2 production and proliferation when combined with IL-12 or I L-1 beta. Conclusions. We conclude that costimulatory activity for activation of rest ing human T cells by nonprofessional donor APC can be delivered through act ivity of bystander recipient-type autologous APC. This mechanism of allosti mulation may contribute to the induction and perpetuation of alloreactivity "in vivo" in a time frame when intragraft professional donor-type APC have been replaced with professional recipient-type APC.