Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154

Abstract

CD154 is a cell surface molecule expressed on activated T cells that binds to CD40, an activating molecule on APCs. Its blockade has been shown to prevent allograft rejection, presumably by interrupting interactions between T cells and APCs. It is known that activated human platelets express and shed CD154 and can induce APC activation and other immune processes in vitro. Here we show that platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of any cellular source of this molecule. CD154-KO mice reject cardiac allografts after receiving CD154-expressing human platelets or recombinant CD154 (rCD154) trimers. Treatment with the human CD154-specific mAb 5c8 specifically prevents this induced rejection. Soluble trimers, but not platelets, induce rejection when infused temporally remote from the surgical procedure, suggesting that surgically induced platelet activation is required for CD154 release. Allograft rejection can thus be instigated by activated platelets through CD154. These data implicate platelets as a proximal component of acquired alloimmunity, providing insight into the mechanisms of allograft rejection and the physiological response to trauma in general.

Effector Mechanisms of Rejection

“…In this context, platelets are believed to act by recruiting mononuclear cells by secreting cytokines/chemokines and by stimulating monocytes, macrophages, and T cells by interaction with them via P-selectin/PSGL-1 or CD40/CD40L pathways (Xu et al 2006;Kirk et al 2009). …”

Platelets as Immune Cells

“…41 Platelet-derived or even soluble CD154 has recently been found to be sufficient for the initiation and induction of vascularized allograft (eg, cardiac) rejection independent of cell-bound sources of this molecule. 42 Platelet-derived sCD40L is also elevated and biologically active in sickle cell anemia. The participation of sCD40L in sickle cell anemia plasma-induced production of B cells, tissue factor, and ICAM-1 suggests that CD40L may contribute to the chronic inflammation and increased thrombotic activity known to occur in this disorder.…”

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge

“…42 Furthermore, adoptively transferred human platelets via CD154 have been shown to cause immune-mediated rejection of allografts in mice. 43 Consistent with an early signaling function in modulation of adaptive immunity, human platelets could support graft rejection only if they were activated at the site of surgery at the time of graft implantation. 43 In our collagen immunization model, we hypothesize that platelets activated at the site of injury express CD154, which is able to stimulate DC maturation and enhance T-cell activation.…”

“…43 Consistent with an early signaling function in modulation of adaptive immunity, human platelets could support graft rejection only if they were activated at the site of surgery at the time of graft implantation. 43 In our collagen immunization model, we hypothesize that platelets activated at the site of injury express CD154, which is able to stimulate DC maturation and enhance T-cell activation. Although we are currently pursuing this question, it is consistent with our initial report that platelets through CD154 can stimulate DCs in vitro, an observation corroborated by several others.…”