Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

Abstract

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade-induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig-resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig-resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell-graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS.

Peritransplant VLA-4 blockade inhibits endogenous memory CD8 T cell infiltration into high-risk cardiac allografts and CTLA-4Ig resistant rejection

“…[9][10][11] Despite activation to express IFN-γ, perforin, and granzyme B within the allograft by 24 hours posttransplant, initial studies indicated that the memory CD8 T cells were unable to mediate sufficient acute graft tissue injury to directly mediate rejection of the allografts. 13,14 In contrast to the ability of peritransplant CTLA-4Ig to markedly prolong survival of allografts subjected to minimal CIS prior to transplant, allografts subjected to prolonged CIS prior to transplant had only a modest enhancement in survival in CTLA-4Ig treated recipients and this CTLA-4Ig resistant rejection was mediated by the infiltration and activation of the endogenous memory CD8 T cells. Indeed, imposition of a longer CIS prior to transplant resulted in a more robust activation of the endogenous donor-reactive memory CD4 and CD8 T cells within the allograft and a marked increase in allograft tissue necrosis by day 5 posttransplant.…”

“…Indeed, imposition of a longer CIS prior to transplant resulted in a more robust activation of the endogenous donor-reactive memory CD4 and CD8 T cells within the allograft and a marked increase in allograft tissue necrosis by day 5 posttransplant. 13,14 In contrast to the ability of peritransplant CTLA-4Ig to markedly prolong survival of allografts subjected to minimal CIS prior to transplant, allografts subjected to prolonged CIS prior to transplant had only a modest enhancement in survival in CTLA-4Ig treated recipients and this CTLA-4Ig resistant rejection was mediated by the infiltration and activation of the endogenous memory CD8 T cells.…”

“…not significantly different allografts was further examined by determining mRNA expression levels of proinflammatory genes associated with the infiltration of these leukocyte populations(Figure 2A,B). Our previous studies indicated that the increased mRNA expression of various proinflammatory cytokine genes in cardiac allografts is accompanied by concomitant increases in the cytokine protein 14. Peritransplant anti-VLA-4 mAb markedly decreased allograft expression of genes associated with effector memory T cell and macrophage activation allo allo + VLA allo allo + γ, TNFα, perforin, granzyme B, and FasL) and graft infiltration (CXCL9/Mig, CXCL10/IP-10, and CCL2/MCP-1).…”

Memory T‐cell exhaustion and tolerance in transplantation

“…Tsuda et al describe the dependence of the effector memory CD8 T cells on CD4 help, specifically through CD40/CD40L interactions with dendritic cells and the production of IL-12p40 homodimers. 96 Their data show that of the inflammatory cytokines produced during prolonged cold ischemia, IL-12p40 has the greatest ability to promote the expansion of endogenous memory CD8 + T cells within the allograft. Blocking IL-12p40 in combination with CTLA-4Ig can decrease the rate of rejection due to cold ischemic time compared with CTLA-4Ig treatment alone.…”

“…Blocking IL-12p40 in combination with CTLA-4Ig can decrease the rate of rejection due to cold ischemic time compared with CTLA-4Ig treatment alone. 96 These studies highlight the impact of inflammation promoted by ischemia and reperfusion on the enhancement of endogenous memory CD8 T-cell responses to allogeneic tissue in the presence of CTLA-4Ig.…”