Activation of alloreactive T cells by allogeneic nonprofessional antigen-presenting cells and interleukin-12 from bystander autologous professional antigen-presenting 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) 1beta, 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-1beta 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-1beta.


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.
de Haan
A
A
Department of Cardiopulmonary Surgery, University Hospital Groningen, The Netherlands.
van der Gun
I
I
van Dijk
E
E
Hepkema
B G
BG
Prop
J
J
de Leij
L F
LF
D000906:Antibodies / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D018106:CD28 Antigens; D007375:Interleukin-1; D007519:Isoantigens; D018664:Interleukin-12