Expression of common gamma chain signalling cytokines and their receptors distinguishes rejection from tolerance in a rat organ transplant model

BackgroundSignalling through the cytokine common γ chain (γc) is crucial for survival of activated T cells. In its absence, severe combined immunodeficiency ensues and transplanted tissues are not rejected.MethodsTo determine whether differences in the availability of γc signalling cytokines correlate with rejection or acceptance, we examined expression of all γc signalling components in organs transplanted between PVG donors and DA recipients. In this combination hearts or kidneys are rejected in < 10 days while livers survive > 100 days. Expression of the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 and their receptors γc, IL-2Rα, IL-2Rβ/IL-15Rβ, IL-4Rα, IL-7Rα, IL-9Rα, IL-15Rα and IL-21Rα was determined by real-time PCR pre-transplant and on days 3, 5 and 7 after transplantation.ResultsMost increased after transplantation, although there were significantly lower levels of IL-2, IL-2Rα, IL-4 and IL-15Rα in tolerant livers compared to rejecting hearts or kidneys. IL-9 was only expressed in normal kidneys and decreased during rejection. IL-15 was constitutively expressed and did not change after transplantation. IL-21 and IL-21R increased in all transplanted organs to a similar extent. IL-7Rα in liver was considerably increased compared with heart or kidney, consistent with its known inverse relationship to global levels of γc signalling.ConclusionsIn transplanted livers, acceptance is associated with low levels of all γc cytokines or receptors except IL-21. This is consistent with “dilution” of γc cytokines from a finite clone size of alloreactive T cells in livers, which are ten times larger than kidneys or hearts.

► First analysis of all components of common γ chain signalling in transplantation. ► Liver transplant tolerance compared to heart / kidney rejection in same rat strain. ► Lower expression of IL-2, IL-4, IL-2Rα and IL-15Rα mRNA associated with tolerance. ► Higher expression of IL-7Rα mRNA in tolerance confirms low γ chain signalling. ► Liver transplant tolerance is associated with limiting γ chain signalling.