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 presented to the recipient's immune system by normal tissue cells, which can be considered to act as nonprofessional antigen-presenting cells (APC). It is well accepted that such nonprofessional APC fail to activate recipient resting T cells due to their inability to deliver costimulatory activity. In our study, we tested a hypothesis that such costimulatory activity may be provided by "bystander" recipient professional APC.

Methods. We set up mixed lymphocyte cultures (MLC) of purified T cell responders and T cell stimulator cells, the latter as nonprofessional APC carrying allogeneic MHC class I and II, and tested if responder-type autologous APC 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 production were investigated.

Results. Autologous APC, i.e., monocytes, were found to facilitate the proliferative response of resting T cells stimulated by allogeneic nonprofessional APC, IL-12 was identified as the most important costimulatory factor for induction of proliferation. IL-1 beta enhanced IL-2 production and proliferation of allostimulated resting T cells but its presence was not essential. Although CD28 triggering alone was ineffective, this costimulatory pathway enhanced IL-2 production and proliferation when combined with IL-12 or IL-1 beta.

Conclusions. We conclude that costimulatory activity for activation of resting human T cells by nonprofessional donor APC can be delivered through activity of bystander recipient-type autologous APC. This mechanism of allostimulation 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.