Endogenous memory T cells with donor-reactivity: early post-transplant mediators of acute graft injury in unsensitized recipients

Abstract

The pretransplant presence of endogenous donor-reactive memory T cells is an established risk factor for acute rejection and poorer transplant outcomes. A major source of these memory T cells in unsensitized recipients is heterologously generated memory T cells expressing reactivity to donor allogeneic MHC molecules. Multiple clinical studies have shown that the pretransplant presence of high numbers of circulating endogenous donor-reactive memory T cells correlates with higher incidence of acute rejection and decreased graft function during the first-year post-transplant. These findings have spurred investigation in preclinical models to better understand mechanisms underlying endogenous donor-reactive memory T-cell-mediated allograft injury in unsensitized graft recipients. These studies have led to the identification of unique mechanisms underlying the activation of these memory T cells within allografts at early times after transplant. In particular, optimal activation to mediate acute allograft injury is dependent on the intensity of ischaemia-reperfusion injury. Therapeutic strategies directed at the recruitment and activation of endogenous donor-reactive memory T cells are effective in attenuating acute injury in allografts experiencing increased ischaemia-reperfusion injury in preclinical models and should be translatable to clinical transplantation.

Keywords: acute T-cell-mediated rejection; costimulation blockade-resistant rejection; ischaemia-reperfusion injury; memory T cells.

Figure 1.. Prolonged cold ischemic storage exacerbates ischemia reperfusion mediated acute graft injury leading to CTLA-4Ig resistant rejection and worse outcomes.

Ischemia reperfusion injury disrupts energy and ion homeostasis in cells and is characterized by decreased ATP production, increased ROS generation and intracellular Ca²⁺ accumulation. These stressors cause cell damage and death with release of DAMPS that perpetuate acute graft injury. Early after graft reperfusion in the recipient, prolonged CIS causes increased pro-inflammatory cytokine and chemokine production, innate immune cell infiltration, and CD4+ and CD8+ T cell activation and differentiation. This more aggressive early post-transplant immune response leads to worse acute graft injury and CTLA-4Ig resistant rejection.

Figure 2.. Endogenous memory T cells with donor reactivity mediate allograft injury.

Prolonged cold ischemic storage causes increased ischemia reperfusion injury, leading to accumulation of ROS, DAMPS, and pro-inflammatory cytokines. Upregulation of key integrins on activated endothelial cells promotes infiltration of donor reactive endogenous CD8+ memory T cells early after graft reperfusion (A). Graft dendritic cells produce p40 homodimers causing increased IL-15 production. Direct trans-presentation and/or release of soluble IL-15/IL-15Rα complex by graft DCs stimulate activation and proliferation of donor-reactive memory T cells within the allograft (B), leading to increased effector functions including release of IFNγ, granzyme B and perforin which results in worse allograft injury (C) and CTLA-4Ig resistant rejection (D).